Decoding TDP-43: the molecular chameleon of neurodegenerative diseases

Zeng, Jixiang; Luo, Chunmei; Jiang, Yang; Hu, Tao; Lin, Bixia; Xie, Yuanfang; Lan, Jiao; Miao, Jifei

doi:10.1186/s40478-024-01914-9

Review
Open access
Published: 31 December 2024

Decoding TDP-43: the molecular chameleon of neurodegenerative diseases

Jixiang Zeng¹^na1,
Chunmei Luo¹^na1,
Yang Jiang¹,
Tao Hu¹,
Bixia Lin¹,
Yuanfang Xie¹,
Jiao Lan¹ &
…
Jifei Miao¹

Acta Neuropathologica Communications volume 12, Article number: 205 (2024) Cite this article

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Abstract

TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43’s crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43’s involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein’s propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington’s disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein’s central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions.

Introduction

TAR DNA-binding protein 43 (TDP-43) is a highly conserved, ubiquitously expressed RNA-binding protein that plays a crucial role in various cellular processes, including transcriptional regulation, RNA splicing, and mRNA stability. Under physiological conditions, TDP-43 is predominantly localized in the nucleus, where it interacts with a wide range of RNA targets and regulates gene expression [1]. The protein contains two RNA recognition motifs (RRMs) and a glycine-rich C-terminal domain, which are essential for its RNA-binding properties and protein-protein interactions, respectively(Fig. 1) [2]. In recent years, TDP-43 has gained significant attention due to its involvement in the pathogenesis of several neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) [3]. In these disorders, TDP-43 is found to be mislocalized to the cytoplasm, where it forms insoluble aggregates and inclusions in affected neurons and glial cells [4]. The mislocalization and aggregation of TDP-43 are believed to contribute to neurotoxicity and cellular dysfunction through various mechanisms, including loss of normal nuclear functions, gain of toxic cytoplasmic functions, and disruption of RNA metabolism [5]. Despite the increasing recognition of TDP-43’s role in neurodegeneration, the precise mechanisms underlying its pathological effects remain elusive. Moreover, the physiological functions of TDP-43 and how their disruption contributes to disease pathogenesis are not fully understood. This review aims to provide a comprehensive overview of the current knowledge on TDP-43 in health and disease, focusing on its physiological and pathological functions, as well as its involvement in the pathogenesis of neurodegenerative disorders. We will also discuss the potential therapeutic strategies targeting TDP-43 and the challenges associated with developing effective treatments for TDP-43-related diseases.

History of TDP-43

The unraveling of TDP-43’s involvement in neurodegenerative conditions has been a gradual process spanning more than 20 years (Fig. 2). Initially identified in 1995 as a protein interacting with the TAR DNA sequence in HIV-1, thus modulating viral gene expression [6], TDP-43’s relevance to neurodegenerative disorders remained unrecognized until 2006. In that year, researchers discovered TDP-43 as a primary constituent of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [7, 8]. This groundbreaking discovery paved the way for the identification of mutations in the TARDBP gene, which codes for TDP-43, as a cause of familial ALS in 2008 [9]. Subsequent investigations revealed that TDP-43 aggregation, resulting in a loss of functional nuclear protein, is present in 95% of ALS cases [10]. The identification of a defect in the C9ORF72 gene in ALS and FTD patients in 2011 further highlighted the complex genetic factors influencing TDP-43 pathology [11]. As knowledge of TDP-43’s role in neurodegeneration expanded, scientists began exploring therapeutic approaches targeting the protein. In 2013, Liu and colleagues engineered peptides targeting TDP-43’s C-terminal domain to reduce its aggregation and toxicity in cells [12]. More recently, in 2020, Mitsubishi Tanabe launched Phase III clinical trials for an oral suspension formulation of edaravone (MT-1186), aiming to provide a more accessible treatment option for ALS patients. While edaravone is an approved treatment for ALS that acts as a free radical scavenger to reduce oxidative stress, it is important to note that it is not specifically designed to target TDP-43 pathology. Instead, it represents a general neuroprotective approach in ALS management. Since 2021 and continuing into 2024, researchers have been actively pursuing various therapeutic strategies targeting TDP-43. These ongoing efforts include facilitating the clearance of TDP-43 aggregates and developing multifunctional peptides for therapeutic applications. Recent advancements have further expanded our understanding of potential interventions, with several promising approaches progressing through preclinical and early clinical stages [13, 14].

Physiological functions of TDP-43

TDP-43 was initially identified as a transcriptional repressor binding to the TAR regulatory element of HIV-1 and influencing transcription factor assembly [6]. TDP-43 also interacts with TGTGTG domains in the promoter region of the mouse SP-10 gene, modulating gene transcription and affecting sperm formation [15], participates in DNA damage response, replication, and genome stability maintenance [16,17,18]. As a splicing factor, TDP-43 regulates the alternative splicing of numerous genes, such as RXRG [19], SC35 [20], SMN [21], the schizophrenia-associated TNIK gene [22], PAR3/NUMB [23], and the cancer stem cell marker CD44 [24], while also suppressing the translation initiation of Map1b, Rac1, and GluR1 mRNAs in cooperation with fragile X syndrome protein (FMRP) [25]. With a vast array of over 4,000 mRNA transcript targets [26], TDP-43 regulates disease-associated transcripts [27] and its own mRNA through a negative feedback loop involving 3’ untranslated region binding [28], and its overexpression can trigger extensive RNA destabilization [29]. TDP-43 exhibits a dual role in RNA stability, promoting mRNA instability for CDK6 [30, 31] and tau [27], while maintaining mRNA stability for G3BP1 [32], Add2 [33], RPTOR/RAPTOR [34], Btn1a1, and Xdh [35], and stabilizing mitochondrial transfer RNA (mt-tRNA) in human mitochondria [36]. The relationship between TDP-43 and tau expression remains a subject of interest, with some studies suggesting that TDP-43 may downregulate tau expression by destabilizing its mRNA transcripts [27] and regulate the ratio of 4-repeat tau to 3-repeat tau through alternative splicing of tau exon 10 [37], although these findings have not been consistently replicated [38]. In addition to its role in RNA and DNA processing, TDP-43 is a crucial participant in the cellular stress response [39,40,41], associating with ribosomes in stress granules during periods of cellular stress to halt translation and promote the synthesis of cytoprotective proteins [42]. The subcellular localization of TDP-43 is dynamic, with regular shuttling between the cytoplasm and nucleus based on transcriptional needs [1], and while low levels of TDP-43 have been detected in the mitochondria of human motor and cortical neurons, in age-matched neurons from patients with ALS and FTLD, the mitochondrial TDP-43 levels are significantly elevated, potentially contributing to altered mitochondrial morphology and impaired function [43].

Role of TDP-43 in DNA interactions and chromatin dynamics

TDP-43 exhibits versatile nucleic acid interactions, demonstrating high affinity for single-stranded DNA (ssDNA) TG repeats, comparable to or surpassing its affinity for UG-repeated RNA sequences. This protein also engages with other ssDNA motifs, such as the HIV TAR element, albeit with altered kinetics relative to (TG)6 stretches [44, 45]. Specifically, surface plasmon resonance (SPR) analyses reveal that TDP-43 interaction with the HIV TAR element exhibits a significantly slower association rate and a moderately faster dissociation rate compared to (TG)6 sequences. These kinetic differences result in a approximately 100-fold lower equilibrium dissociation constant (KD) for the HIV TAR element compared to (TG)6, indicating substantially reduced binding affinity [46]. Although research has predominantly focused on TDP-43’s RNA-binding capabilities, multiple studies have established its interaction with double-stranded DNA (dsDNA) [44, 47], particularly at free dsDNA termini [18]. Emerging evidence highlights TDP-43’s capacity to recognize specific DNA sequences within promoter regions, thereby modulating the expression of various genes [48,49,50,51,52,53,54,55,56]. While the precise mechanisms underlying TDP-43’s involvement in chromatin-related processes remain to be fully elucidated, it has become increasingly apparent that disruptions in TDP-43 function can profoundly impact chromatin homeostasis [57]. Recent studies have shed light on this complex interplay. Yamanaka et al. demonstrated that TDP-43 monomerization, an early event in ALS pathology, leads to cytoplasmic mislocalization, potentially impairing its nuclear functions in pre-mRNA splicing and chromatin remodeling [56]. Concurrently, Arseni et al. identified a distinct “chevron fold” in TDP-43 aggregates in type A FTLD-TDP, along with novel post-translational modifications such as citrullination and mono-methylation at arginine residue 293 [58]. These structural and biochemical alterations may disrupt nucleosome dynamics, nuclear matrix organization, and protein-DNA interactions, collectively perturbing chromatin structure and gene expression. The consequences of these TDP-43-mediated chromatin disruptions are far-reaching, potentially including alterations in neuronal gene expression profiles, impairment of DNA damage repair mechanisms, and dysregulation of activity-dependent gene expression. Such perturbations could contribute to the progressive nature of neurodegenerative diseases by compromising neuronal plasticity and increasing vulnerability to cellular stressors. As ongoing investigations continue to unravel the multifaceted nature of TDP-43, researchers anticipate gaining deeper insights into its role in transcriptional regulation and chromatin remodeling. This enhanced understanding may shed light on the toxic effects associated with altered TDP-43 function, potentially opening new avenues for therapeutic interventions targeting TDP-43 dimerization/multimerization or its post-translational modifications to maintain chromatin homeostasis and slow disease progression in conditions such as ALS and FTLD.

TDP-43’s involvement in chromatin silencing and transcriptional regulation

TDP-43 plays a crucial role in transcriptional regulation and chromatin dynamics, acting as both a repressor and an activator depending on the cellular context (Fig. 3). This dual function significantly contributes to maintaining cellular homeostasis and has important implications for neurodegenerative processes.

In its repressive role, TDP-43 can bind to promoter regions and interfere with promoter-enhancer interactions. For example, in mouse spermatocytes, TDP-43 represses the Acrv1 gene by binding to two GTGTGT motifs in its promoter. This binding recruits TDP-43 to the nuclear matrix, which physically sequesters the Acrv1 promoter away from transcriptional machinery and enhancers. The GTGTGT motifs are critical for this repression, as mutation of these sites leads to premature expression of Acrv1 in spermatocytes, likely due to the promoter’s release from the repressive nuclear matrix environment [55]. Conversely, TDP-43 can activate gene expression in certain contexts. In human monocytic cells, TDP-43 binds to a 66 bp region of the TNF-alpha promoter (between − 550 and − 487) that lacks NF-κB binding sites but shows LPS-induced transcriptional activity. TDP-43 cooperates with NF-κB to enhance TNF-alpha expression in response to LPS stimulation [54]. In SH-SY5Y cells, TDP-43 directly binds to and activates the CHOP promoter, with this activation abolished by deletion of TDP-43’s RNA recognition motifs (RRM1 and RRM2) or by acetylation-mimicking mutations [48]. These examples demonstrate that TDP-43 can function as a sequence-specific transcriptional activator, with its effects modulated by stimuli like LPS and post-translational modifications such as acetylation. The interaction between TDP-43 and chromatin remodeling complexes has emerged as a key mechanism in its regulatory function. Suppressor screens have revealed that a significant proportion of TDP-43 toxicity modulators are involved in chromatin remodeling, particularly those associated with the Trithorax and SWI/SNF complexes [59]. Physical interactions between TDP-43 and chromatin remodelers like Chd1 (in Drosophila) and CHD2 (in humans) appear to interfere with their normal association with chromatin at specific gene loci [59, 60]. In Drosophila, TDP-43 reduces Chd1 recruitment to heat shock genes like Hsp70 upon stress, impairing nucleosome clearance and activation of these genes. In human cells, TDP-43 interacts predominantly with CHD2 in the soluble nuclear fraction, potentially sequestering it away from chromatin. This interference with chromatin remodeler function, particularly at stress-responsive genes, may contribute to the impaired stress response and increased cellular vulnerability seen in TDP-43 proteinopathies. The cellular context significantly influences TDP-43 activity and its interactions with chromatin remodeling complexes. Studies in mouse motor neurons expressing ALS-linked TDP-43 mutations have shown significant reductions in nuclear levels of key nBAF chromatin-remodeling complex subunits, including Brg1, BAF53b, and CREST. These alterations were associated with cytoplasmic accumulation of mutant TDP-43 [61]. The loss of these crucial nBAF components likely disrupts proper chromatin remodeling, potentially affecting gene expression patterns, dendritic morphology, and synaptic function. These findings collectively point to a central role for TDP-43 in maintaining cellular homeostasis through its involvement in transcriptional regulation and chromatin dynamics. Moreover, TDP-43 interacts with long non-coding RNAs (lncRNAs) to regulate gene expression. In muscle cells, TDP-43 interacts with the lncRNA Myolinc to bind to promoter regions of numerous genes essential for muscle differentiation. Specifically, ChIP-seq and ChIP-PCR analyses revealed that the TDP-43-Myolinc complex binds to promoters of key myogenic regulatory factors and muscle-specific genes, including MyoD, Acta1, Ccnd1, Tnnc1, and Tnni1. The binding of TDP-43 to these promoters was significantly reduced upon Myolinc knockdown. MyoD is a master regulator of myogenesis, while Acta1, Tnnc1, and Tnni1 are crucial structural components of the muscle contractile apparatus. Ccnd1 regulates cell cycle progression during myoblast proliferation and differentiation. By modulating the expression of these genes, the TDP-43-Myolinc interaction plays a critical role in coordinating the myogenic differentiation program, from the initial activation of myogenic regulatory factors to the expression of muscle-specific structural proteins [53]. This interaction highlights the complexity of TDP-43’s role in transcriptional regulation and its potential tissue-specific functions.

Beyond its direct involvement in gene regulation, TDP-43 plays a crucial role in maintaining genome stability through the regulation of retrotransposons (Fig. 3). Studies have shown that TDP-43 is involved in silencing retrotransposons through multiple mechanisms. TDP-43 directly binds to retrotransposon-derived RNAs, particularly those from LINE-1 elements, and recruits nuclear RNA degradation complexes such as the nuclear exosome targeting (NEXT) complex, promoting their degradation [62]. Additionally, TDP-43 contributes to the maintenance of heterochromatin at retrotransposon loci, further suppressing their activity [63]. Loss of TDP-43 function can lead to increased retrotransposon activity, which has several detrimental consequences for genome stability and cellular function. In TDP-43 depleted cells, there is a significant decondensation of heterochromatin at retrotransposon loci, leading to increased retrotransposon expression and potential mobilization [63]. This elevated retrotransposon activity can result in insertional mutagenesis, potentially disrupting gene function or regulatory elements. Moreover, the accumulation of retrotransposon-derived RNA and cDNA can trigger DNA damage responses and cellular stress, potentially contributing to neurodegeneration in conditions such as ALS and FTD [64]. This function of TDP-43 in genome maintenance adds another layer to its importance in cellular homeostasis and potentially in neurodegenerative processes.

TDP-43’s role in histone modifications and chromatin remodeling complexes

Recent investigations into TDP-43’s role in epigenetic regulation have unveiled a complex interplay between this protein and various chromatin-modifying processes. Studies utilizing human neuroblastoma SH-SY5Y cells have revealed genotype-specific alterations in histone modifications, with TDP-43M337V and wild-type TDP-43 differentially affecting H3S10Ph-K14Ac and H3K9me3 levels, respectively [65]. These findings suggest a nuanced impact of TDP-43 variants on transcriptional regulation via histone tail modifications. Drosophila-based RNAi screens have further elucidated the connection between TDP-43 toxicity and chromatin state. The identification of histone-modifying enzymes and chromatin remodelers as modifiers of TDP-43 toxicity suggests a mechanism involving impaired nucleosome dynamics at stress-responsive genes. Specifically, TDP-43 interferes with the recruitment of the chromatin remodeler Chd1 to heat shock genes like Hsp70, leading to reduced nucleosome clearance and impaired gene activation upon stress. This disruption of chromatin remodeling, rather than changes in global H3K4me3 levels, appears to be a key aspect of TDP-43-mediated toxicity [60]. The suppression of Su(var)3–9, the Drosophila homolog of human SUV39H1 and a histone methyltransferase responsible for H3K9 trimethylation, alleviates TDP-43-induced toxicity. This finding aligns with the observed increase in H3K9me3 levels upon TDP-43WT overexpression in cellular models. Specifically, Masala et al. demonstrated that overexpression of wild-type TDP-43 in SH-SY5Y cells leads to increased H3K9me3, a repressive histone mark associated with heterochromatin formation. The fact that reducing the enzyme responsible for this modification (Su(var)3–9) mitigates TDP-43 toxicity suggests that aberrant H3K9 trimethylation may contribute to TDP-43-mediated neurodegeneration. This interaction highlights the importance of maintaining proper epigenetic regulation, particularly of repressive histone marks, in the context of ALS pathogenesis [60, 65] (Fig. 3).

Recent advances have shed light on TDP-43’s interaction with chromatin, particularly at R-loops. Giannini et al. demonstrated that TDP-43 plays a crucial role in R-loop homeostasis and R-loop-mediated DNA damage [16]. This interaction is critical for maintaining genome stability, and its disruption in ALS models led to increased DNA damage, providing a novel perspective on TDP-43’s role in chromatin dynamics and genome integrity. Histone deacetylases (HDACs) have emerged as key players in TDP-43 regulation and pathology. HDAC1 silencing mitigates TDP-43-induced toxicity, potentially through direct modulation of TDP-43 acetylation and subsequent alterations in its cellular distribution and function [48]. In Drosophila models of TDP-43 proteinopathy, HDAC6 overexpression has demonstrated neuroprotective effects through multiple mechanisms. HDAC6 reduces insoluble poly-ubiquitinated proteins by facilitating their autophagic degradation. Specifically, HDAC6 overexpression significantly increased LC3-I/II levels in TDP-43-overexpressing cells, indicating enhanced autophagy activation. Additionally, HDAC6 overexpression decreased both cytoplasmic and nuclear TDP-43 protein levels, suggesting it may regulate TDP-43 localization and aggregation. These effects collectively led to improved lifespan and motor function in TDP-43/ATXN2 flies. Importantly, HDAC6’s role in modulating TDP-43 activity appears to be independent of its deacetylase function, as inhibition of HDAC6’s enzymatic activity did not affect TDP-43 protein levels. Rather, HDAC6 seems to act as a mediator between the ubiquitin-proteasome system and the autophagy-lysosome pathway, promoting the clearance of insoluble TDP-43 aggregates through autophagy when the proteasome is impaired [66]. Furthermore, studies on nBAF proteins in mouse motor neurons expressing ALS-linked mutant TDP-43 have provided additional evidence for TDP-43’s involvement in chromatin remodeling. Nuclear depletion of TDP-43 can lead to decreased production of nBAF subunits, potentially through transcriptional repression or disrupted RNA processing, which may contribute to dendritic atrophy and neurodegeneration [61]. These findings collectively highlight the intricate relationship between TDP-43 and epigenetic mechanisms, underscoring the protein’s multifaceted role in neuronal homeostasis and disease pathogenesis.

TDP-43’s influence on dna methylation and transcriptional machinery

Recent studies have uncovered significant alterations in DNA methylation patterns in ALS patients [67]. However, the nature and consistency of these changes vary across studies. Post-mortem analyses of brain tissues revealed elevated 5mC and 5hmC levels in surviving lower motor neurons in ALS cases compared to controls. However, within ALS cases, neurons exhibiting pathological nuclear TDP-43 loss showed reduced levels of both 5mC and 5hmC compared to neurons with normal nuclear TDP-43 localization. This inverse relationship between TDP-43 pathology and DNA methylation suggests a potential link between TDP-43 function and epigenetic regulation. TDP-43 is known to bind DNA and regulate gene expression, including genes involved in neuronal survival and mitochondrial homeostasis. The loss of nuclear TDP-43 may therefore disrupt normal methylation patterns, potentially contributing to altered gene expression and RNA processing in affected motor neurons [68]. This correlation suggests a potential link between TDP-43 localization and DNA methylation status, possibly influencing RNA processing and splicing in affected motor neurons. A comprehensive review by Masala et al. highlighted the complexity of epigenetic alterations in ALS, reporting both hyper- and hypomethylated sites across different studies [65]. These discrepancies may be attributed to differences in tissue types examined, disease stages, or methodological approaches, underscoring the need for further research to reconcile these findings. Advanced multi-omics and machine learning approaches have further elucidated ALS-specific epigenetic signatures in iPSC-derived motor neurons. Differentially methylated regions (DMRs) were identified across various ALS subtypes, including those associated with C9orf72, FUS, SOD1 and TARDBP mutations [69]. While the methylation patterns varied among different ALS mutations, highlighting the heterogeneity of the disease, there was a significant convergence towards synaptic-related genes across all subtypes. This epigenetic dysregulation of synaptic genes suggests that synaptic dysfunction may be a common pathological mechanism in ALS, regardless of the underlying genetic cause. Furthermore, genes involved in acetylcholine receptor binding were consistently hypomethylated across all ALS subtypes, potentially affecting neuromuscular junction function [69]. These findings provide insight into how epigenetic alterations may contribute to ALS pathology by modulating gene expression and synaptic processes, and underscore the complex interplay between genetic mutations, epigenetic changes, and transcriptional dysregulation in the heterogeneous landscape of ALS [69]. The interaction between TDP-43 and methyl CpG-binding protein 2 (MeCP2) (Fig. 3), as revealed by proteomic analysis, hints at a broader role for TDP-43 in epigenetic regulation [26, 70]. Furthermore, genetic screens have identified numerous transcriptional machinery components as modifiers of TDP-43-related phenotypes, including transcription elongation factors and mediator complex subunits [59, 71, 72]. Transgenic mouse models expressing wild-type or mutant TDP-43 lacking nuclear localization signals have demonstrated extensive gene expression changes, particularly affecting nucleosome protein-coding genes and transcription-related pathways [73]. RNA-seq analyses have revealed alterations in histone transcript levels and differential splicing of chromatin-related genes, suggesting a role for TDP-43 in histone transcript regulation [72]. These findings collectively point to TDP-43 as a key epigenetic regulator with the capacity to modulate chromatin structure, transcriptional processes, and DNA damage/repair pathways. The extensive network of TDP-43-associated chromatin factors (Table 1) underscores its significance in maintaining epigenetic homeostasis.

Table 1 Chromatin and transcription factors regulated by TDP-43

Full size table

Role of TDP-43 in RNA metabolism

TDP-43 interactome and splicing regulation

Recent advancements in proteomics, functional genomics, and high-throughput sequencing have significantly enhanced our understanding of TDP-43’s multifaceted role in RNA metabolism, particularly in splicing regulation. Studies investigating the TDP-43 interactome have revealed complex protein networks involved in transcription, translation, and RNA processing, shedding light on the intricate molecular mechanisms underlying TDP-43 function.

Interactome analyses have highlighted differences between wild-type and mutant TDP-43, suggesting that disease-causing mutations may disrupt critical protein-protein interactions [74, 75]. These alterations potentially contribute to ALS pathogenesis by affecting mRNA splicing, export, and translation. The identification of distinct nuclear and cytoplasmic TDP-43 interaction networks underscores the protein’s diverse cellular functions and its importance in maintaining RNA homeostasis.

TDP-43’s influence on alternative splicing encompasses a wide range of mechanisms, including exon skipping, alternative splice site selection, regulation of mutually exclusive exons, intron retention, and alternative promoter usage. The development of comprehensive TDP-43 RNA target libraries has provided valuable insights into its splicing functions and potential biomarkers for TDP-43-related disorders [76,77,78]. One notable target, HNRNPA1, exemplifies how TDP-43 can modulate alternative splicing by repressing specific splice site usage [23]. Post-translational modifications (PTMs) of TDP-43 have emerged as crucial regulators of its splicing activity. Phosphorylation, SUMOylation, O-GlcNAcylation, and acetylation have been shown to modulate TDP-43’s ability to regulate splicing events [79,80,81,82,83,84]. These modifications can affect TDP-43’s structure, localization, and interactions with target RNAs and other proteins, ultimately impacting its splicing regulatory function. For instance, phosphorylation at Ser48 influences TDP-43 polymerization and splicing activity, while SUMOylation and O-GlcNAcylation affect its ability to regulate specific transcripts [81]. Studies utilizing mouse models expressing ALS-linked TDP-43 mutations have revealed splicing abnormalities in various target mRNAs, highlighting the potential role of splicing dysregulation in disease pathogenesis [85, 86]. Comparative analyses of RNA-sequencing data from TDP-43-depleted models and human ALS/FTD samples have identified shared transcriptional patterns and differential exon usage events, providing new avenues for targeted investigations [87]. The identification of common splicing alterations in genes such as STMN2 and POLDIP3 offers potential biomarkers for TDP-43 dysfunction. The regulation of alternative polyadenylation (APA) by TDP-43 has also gained attention as a potential mechanism influencing gene expression in health and disease [88,89,90]. Changes in APA patterns can affect mRNA stability and protein levels, suggesting a broader impact of TDP-43 dysfunction on cellular homeostasis. For example, alterations in the APA of NEFL and TMEM106M have been observed in TDP-43 knockdown neurons, resulting in changes in their protein expression levels [88].

Recent studies have also uncovered a potential link between TDP-43 splicing regulation and the presence of abnormal cytoplasmic intron retention in ALS models [91]. This finding suggests that retained introns may act as RNA regulators, influencing the homeostatic control of RNA-binding protein localization during development and disease progression.

Future research directions should focus on elucidating the specific splicing events affected by TDP-43 mutations and identifying genes susceptible to TDP-43-mediated APA regulation. Additionally, investigating the interplay between TDP-43 PTMs and its splicing function may provide insights into potential therapeutic targets. The development of novel biomarkers based on TDP-43-dependent splicing events could improve early diagnosis and monitoring of disease progression in ALS and related neurodegenerative disorders. Furthermore, exploring the role of TDP-43 in regulating non-coding RNAs and its potential involvement in phase separation processes within stress granules may uncover new aspects of its function in cellular stress responses and neurodegeneration. Integrating these findings with structural biology approaches to understand the molecular basis of TDP-43 aggregation could lead to innovative strategies for preventing or reversing pathological TDP-43 accumulation.

Cryptic exon inclusion and TDP-43 dysfunction

The identification of cryptic exons (CEs) has revolutionized our understanding of TDP-43-related neurodegeneration. These typically silenced genomic elements, when aberrantly incorporated into mature transcripts, serve as molecular signatures of TDP-43 dysfunction in various neurodegenerative conditions [92]. TDP-43’s role in maintaining genomic integrity through CE suppression involves complex interactions with UG-rich regions(Fig. 4). The disruption of this regulatory mechanism triggers a cascade of events affecting protein synthesis and cellular homeostasis. The species-specific nature of CEs underscores the critical importance of selecting appropriate model systems for studying TDP-43 pathologies, as minor genetic variations between species can lead to significant differences in TDP-43 binding and function [92]. Key genes affected by CE inclusion, such as STMN2, UNC13A, ERMN, and Nfasc, play pivotal roles in neuronal survival and function [93,94,95,96,97,98]. The inclusion of CEs in these transcripts can result in frameshifts, premature stop codons, and reduced levels of functional proteins. For instance, STMN2, highly expressed in spinal motor neurons, experiences aberrant splicing due to TDP-43 dysfunction, leading to impaired axonal growth and regeneration – a hallmark of ALS pathogenesis [99, 100]. The discovery of ALS/FTD risk factors in the non-coding region of UNC13A, coinciding with a CE location, highlights the intricate interplay between genetic susceptibility and TDP-43-mediated splicing regulation [94]. This finding opens new avenues for investigating the genetic basis of neurodegenerative diseases. Emerging therapeutic strategies targeting CE inclusion show promise in treating TDP-43 proteinopathies. Antisense oligonucleotides (ASOs) have demonstrated potential in suppressing cryptic splicing and restoring axonal function in TDP-43-deficient motor neurons [101]. These approaches could pave the way for novel treatments not only for ALS and FTD but potentially for a broader spectrum of neurodegenerative conditions associated with TDP-43 pathology.

The detection of CE-derived peptides in patient cerebrospinal fluid represents a significant breakthrough in biomarker development [102]. These cryptic peptides, identifiable through specially developed monoclonal antibodies [103], offer new possibilities for monitoring disease progression and assessing therapeutic efficacy in ALS/FTD spectrum disorders. Intriguingly, the presence of CEs in STMN2 and UNC13A transcripts has been observed in AD brain tissue, correlating with TDP-43 pathology burden [104, 105]. This observation expands the relevance of TDP-43-mediated CE regulation beyond ALS and FTD, suggesting a more widespread role in neurodegenerative processes.

Circular RNAs and TDP-43 splicing dysregulation

The unique non-coding RNA molecules, formed through back-splicing, have emerged as critical players in cellular function and potential biomarkers for various disorders [106, 107]. CircRNAs possess remarkable stability due to their closed-loop structure, which confers resistance to exonuclease degradation. This characteristic, combined with their tissue-specific expression patterns, makes them particularly promising candidates for biomarker development in neurodegenerative diseases [108,109,110,111]. The biogenesis of circRNAs involves complex mechanisms reliant on canonical splicing machinery. Three primary routes have been identified: intron-pairing-driven circularization, RNA-binding protein (RBP)-mediated formation, and lariat-driven circularization [112,113,114]. These processes underscore the intricate relationship between circRNA formation and other aspects of RNA processing.

In the context of TDP-43-related neurodegenerative diseases, circRNAs have garnered significant attention. RNA-seq analyses of TDP-43 mouse models with forebrain-specific TARDBP gene deletion have revealed substantial alterations in circRNA expression profiles within the neocortex [115]. Specifically, 182 circRNAs showed significantly different expression levels between TDP-43 cKO and control mice, with 22 circRNAs altered at both 3 and 12 months of age [116, 117]. Notably, circRNAs derived from genes involved in synaptic function (e.g. Dlg3, Snap91) and RNA processing (e.g. Sort1, Camk1g) were dysregulated. The aberrant splicing of Sort1, leading to accumulation of a non-functional isoform, and the inclusion of cryptic exons in transcripts like Camk1g, highlight potential mechanisms by which TDP-43 loss affects circRNA biogenesis and function. This finding suggests a complex link between TDP-43 function and circRNA regulation, likely mediated through TDP-43’s roles in pre-mRNA splicing and suppression of cryptic exon inclusion. The loss of TDP-43 may disrupt normal splicing dynamics, leading to altered circRNA production and potentially contributing to neuronal dysfunction in TDP-43 proteinopathies. Studies focusing on peripheral blood mononuclear cells from sporadic ALS patients have identified differentially expressed circRNAs, indicating their potential utility as blood-based biomarkers for the disease. For instance, hsa_circ_0023919 (derived from PICALM gene), hsa_circ_0063411 (from TNRC6B gene), and hsa_circ_0088036 (from SUSD1 gene) were found to be significantly dysregulated in ALS patients and showed high diagnostic potential with AUC values > 0.95. Interestingly, hsa_circ_0023919 contains binding sites for miR-9, which is upregulated in ALS, suggesting a potential disease-relevant interaction. These circRNAs may reflect systemic RNA processing alterations in ALS, although the exact mechanisms linking them to TDP-43 dysfunction require further investigation [116, 117]. These discoveries pave the way for the development of non-invasive diagnostic and prognostic tools in ALS and related disorders, potentially revolutionizing clinical management strategies. The relationship between TDP-43 and circRNA formation is particularly intriguing given TDP-43’s crucial role in splicing regulation. As circRNA biogenesis heavily relies on splicing machinery, alterations in TDP-43 function could have far-reaching effects on circRNA landscapes across various tissues. This interplay may contribute to the complex pathophysiology observed in TDP-43-related neurodegenerative conditions.

TDP-43 and miRNA regulation

MicroRNAs (miRNAs) represent a class of small, non-coding RNA molecules that play a crucial role in post-transcriptional gene regulation. These approximately 22-nucleotide sequences exert their regulatory effects by binding to the 3’ untranslated regions (UTRs) of target mRNAs, typically resulting in translational repression or mRNA degradation [118]. The relationship between TDP-43 and miRNA biogenesis has emerged as an area of significant interest in the field of neurodegenerative research. TDP-43 has been implicated in both the canonical and non-canonical pathways of miRNA production, suggesting a multifaceted role in miRNA regulation. In the canonical pathway, TDP-43 participates in miRNA biogenesis within both the nucleus and cytoplasm. Its involvement in various stages of miRNA processing highlights the protein’s versatility in RNA metabolism. The non-canonical pathway, interestingly, involves the spliceosome machinery, where TDP-43’s splicing regulatory function may influence the conversion of miRtrons into intron lariats [119, 120]. These lariats are subsequently processed by debranching enzyme 1 (DBR1) to generate pre-miRNAs, further emphasizing the intricate connection between splicing regulation and miRNA production [121].

Recent studies have revealed TDP-43’s association with the regulation of diverse miRNAs across various experimental models and in ALS patients. For instance, in TDP-43 knockdown Hep-3B cells, alterations in miR-let-7b and miR-663 levels were observed [122]. HEK293T cells with reduced nuclear TDP-43 localization exhibited changes in miR-27b-3p and miR-181c-5p expression [123]. In the clinical context, plasma samples from TARDBPG376D-associated ALS patients showed dysregulation of miR-132–5p, miR-132–3p, miR-124–3p, and miR-133a-3p [124]. Animal models have also provided valuable insights. In transgenic TDP-43Q331K mice, alterations in miR-122–5p and miR-486b-5p levels were detected in extracellular vesicles derived from both cortical tissue and serum [125]. These findings collectively underscore the widespread impact of TDP-43 dysfunction on miRNA regulation across different biological systems.

Despite these observations, the precise mechanisms underlying miRNA dysregulation in TDP-43-related pathologies remain elusive. It is unclear whether the observed changes stem from direct TDP-43 splicing dysregulation affecting miRNA production through the non-canonical pathway, alterations in the canonical miRNA biogenesis pathway involving TDP-43, or alternative, yet-to-be-identified mechanisms. The complex interplay between TDP-43 and miRNA regulation opens up new avenues for understanding the molecular basis of neurodegenerative diseases.

TDP-43 in disease

The multifaceted pathogenesis of TDP-43

TDP-43-related disorders present a complex challenge in neurodegenerative research, characterized by intricate molecular and cellular dysfunctions. The pathogenesis of these conditions arises from a delicate interplay between protein misregulation, cellular stress responses, and systemic alterations in neuronal and glial function [126]. At the molecular level, TDP-43’s multifaceted role in RNA processing magnifies the consequences of its dysregulation [127,128,129]. Aberrations in splicing patterns, transcriptional control, and mRNA stability reverberate throughout the cellular transcriptome, potentially affecting an extensive array of genes crucial for neuronal health and function [130, 131]. This widespread impact underscores the protein’s pivotal role in maintaining cellular homeostasis and highlights the far-reaching effects of its dysfunction. The formation of pathological TDP-43 aggregates serves as a hallmark of these disorders [5, 127, 132, 133]. These insoluble structures not only sequester functional protein but also interfere with various cellular processes, including the dynamics of stress granules and RNA transport [127, 134]. The prion-like behavior exhibited by these aggregates facilitates their intercellular spread, offering a potential explanation for the progressive nature of TDP-43 proteinopathies and the observed pattern of pathology progression in affected brain regions [135,136,137,138].

Mitochondrial impairment emerges as a critical feature in TDP-43 pathology. TDP-43’s interaction with mitochondrial components disrupts energy production, calcium homeostasis, and organelle dynamics [139,140,141,142,143]. This energetic crisis, coupled with increased oxidative stress, creates an environment particularly detrimental to the high energy demands of neurons(Fig. 5) [144]. The resulting metabolic disturbances may contribute significantly to the energy deficits observed in affected neural tissues. The non-cell autonomous nature of TDP-43 disorders is evident in the dysfunction of glial cells, particularly astrocytes and microglia [144,145,146,147]. Altered glial function compromises metabolic support to neurons and triggers neuroinflammatory responses, exacerbating the neurodegenerative process [144, 148,149,150,151]. The downregulation of key signaling pathways and metabolite transporters in glial cells may impair their ability to provide essential support to neurons, further contributing to the progression of neurodegeneration.

Epigenetic alterations associated with TDP-43 dysfunction add another layer of complexity to the disease mechanism [48, 152, 153]. The interaction between TDP-43 and histone modifiers, such as HDAC6, suggests far-reaching effects on gene expression patterns and cellular physiology. These epigenetic changes may contribute to the long-term alterations in gene expression observed in TDP-43 proteinopathies and could represent potential targets for therapeutic intervention. The protein quality control systems, including the ubiquitin-proteasome system and autophagy, are significantly impacted by TDP-43 pathology [140, 154]. Hyperphosphorylation of TDP-43 interferes with ubiquitin-mediated degradation, while downregulation of the protein impairs autophagy and mitophagy processes [155]. This disruption in protein quality control can lead to the accumulation of toxic protein species, further exacerbating cellular dysfunction.

The temporal sequence and interdependencies of these pathogenic events remain a significant challenge in the field. Elucidating whether certain mechanisms represent primary drivers or secondary consequences of TDP-43 pathology could provide crucial insights for developing targeted interventions. The complex interplay between these various pathogenic pathways suggests that effective therapies may need to address multiple aspects of the disease process simultaneously.

The intricate regulatory role of TDP-43 in cancer

The role of TDP-43 in oncogenesis has emerged as a complex and intriguing area of research, revealing its multifaceted involvement in various cancer types [156, 157]. TDP-43 has shown both pro-tumorigenic and tumor-suppressive functions, depending on the cellular context and cancer type. In mammary neoplasms, TDP-43 exhibits oncogenic properties, influencing tumor progression through Wnt/β-catenin and multiple other pathways [158,159,160]. Its interaction with CD44 pre-mRNA regulates alternative splicing, potentially impacting cancer stem cell dynamics [24]. This finding underscores the protein’s capacity to modulate key cellular processes involved in tumor initiation and progression. Pulmonary malignancies also demonstrate TDP-43’s oncogenic potential. Its regulation of MALAT1 expression and its role as a downstream effector of lncRNA MIAT contribute to metastatic processes in non-small cell lung cancer [161]. Furthermore, TDP-43’s involvement in therapy resistance mechanisms, particularly in relation to EGFR-TKIs, highlights its clinical relevance in lung cancer treatment strategies [162, 163]. Hepatocellular carcinoma research has revealed TDP-43’s influence on metabolic reprogramming. The protein’s regulation of glycolysis through miRNA-mediated mechanisms underscore its role in modulating cancer cell energy dynamics, it could upregulate lipid metabolism to suppress apoptosis in hepatocellular carcinoma [164,165,166]. Additionally, TDP-43’s involvement in epithelial-mesenchymal transition via the Wnt/β-catenin pathway emphasizes its significance in metastatic processes [167]. In glioblastoma multiforme, TDP-43’s interaction with HDAC6 promotes tumor progression and activates autophagy, enhancing cancer cell survival under nutrient-deprived conditions [168]. This finding illuminates the protein’s role in cellular stress responses within the tumor microenvironment. Melanoma studies have implicated TDP-43 in cell proliferation and migration, potentially through its effects on glucose metabolism [164]. This observation further supports the involvement of TDP-43 in cancer-related metabolic alterations.

Contrastingly, TDP-43 exhibits tumor-suppressive properties in certain contexts. Its association with TRIM16-induced cancer cell death in neuroblastoma and breast cancer suggests a protective role [162, 163]. Its ability to induce G₂/M arrest and cell death via p53-dependent mechanisms in cervical cancer cells further exemplifies its potential tumor-suppressive functions [157, 169]. The dual nature of TDP-43 in cancer is further illustrated by its complex regulation of cancer-related miRNAs, simultaneously promoting and inhibiting oncogenic processes through different miRNA targets [170]. This intricate regulatory network underscores the context-dependent nature of TDP-43’s effects on cancer progression. Cell type-specific effects of TDP-43 on downstream genes, such as its differential regulation of CDK6 in various cell lines, highlight the importance of cellular context in determining its oncogenic or tumor-suppressive roles [30, 31]. The heterogeneity of cancer and the intricate regulatory role of TDP-43 in tumor progression emphasize the need for continued research to elucidate the precise mechanisms underlying its context-dependent functions in different cancer types.

TDP-43 in neurodegenetive disease

Amyotrophic lateral sclerosis (ALS)

ALS represents a formidable challenge in the realm of neurodegenerative disorders, characterized by the progressive deterioration of motor function due to the loss of upper and lower motor neurons [85, 136, 171, 172]. This condition manifests in two primary forms: sporadic ALS (sALS), accounting for the vast majority of cases, and familial ALS (fALS), which is often linked to genetic mutations, particularly in the TDP-43 gene [173, 174]. A hallmark of ALS pathology is the widespread presence of TDP-43 abnormalities, observed in over 95% of patients [141, 175]. This pathological signature involves the depletion of nuclear TDP-43 and the accumulation of cytoplasmic aggregates composed of hyperphosphorylated, ubiquitinated, and cleaved TDP-43 proteins [129, 147]. The progression of TDP-43 pathology in ALS follows a distinct anatomical pattern, initiating in the motor cortex and brainstem motor nuclei before expanding to other regions [176,177,178]. This staged progression begins in the agranular motor cortex and specific cranial nerve nuclei, subsequently involving the prefrontal neocortex and brainstem structures. As the disease advances, it extends to the basal ganglia, temporal lobe, and finally impacts areas such as the substantia nigra and cerebellar nuclei. TDP-43 mislocalization, particularly evident in the motor and frontal cortices, contributes to cortical hyperexcitability and altered neurotransmission [179, 180]. These neurophysiological changes underpin the motor and cognitive deficits characteristic of ALS, highlighting the broad impact of TDP-43 dysfunction on neuronal function.

The pathogenesis of TDP-43-related ALS is intricately linked to mutations in various ALS-associated genes. These genetic alterations disrupt crucial cellular processes, including axonal transport, leading to the formation and propagation of TDP-43 proteinopathy [181, 182]. The spread of pathological TDP-43 from the cortex to other neural regions occurs through synaptic transmission, suggesting a prion-like mechanism of disease progression. Mutations in the C9orf72 gene, a common genetic factor in ALS, further complicate the picture by affecting nucleocytoplasmic transport [183]. This disruption interferes with the normal autoregulation of TDP-43 [184], exacerbating its mislocalization and aggregation. The impact of TDP-43 pathology extends beyond neurons to glial cells, particularly oligodendrocytes [95]. These cells, crucial for providing metabolic support to neurons through monocarboxylic transporters like MCT1, are compromised by TDP-43 deposition [176, 177]. This glial dysfunction contributes to the overall neuronal loss observed in ALS, underscoring the complex, multicellular nature of the disease process.

Understanding the intricate interplay between genetic factors, protein aggregation, and cellular dysfunction in ALS provides a foundation for developing targeted therapeutic strategies. The multifaceted role of TDP-43 in ALS pathogenesis highlights its potential as a key target for future interventions aimed at slowing or halting disease progression.

Frontotemporal lobar degeneration (FTLD)

FTLD represents a complex spectrum of neurodegenerative disorders characterized by progressive deterioration of behavior, language, and motor function [185]. This multifaceted condition encompasses several clinical syndromes, each with distinct pathological and genetic underpinnings. The neuropathological classification of FTLD reveals three primary subtypes based on the predominant protein aggregates: FTLD-TDP-43, FTLD-tau, and FTLD-FUS [186]. Among these, TDP-43 pathology has emerged as a significant hallmark, present in approximately half of all FTLD cases, despite TDP-43 mutations being relatively rare in this patient population [187]. The anatomical distribution of TDP-43 pathology strongly correlates with specific clinical phenotypes within the FTLD spectrum. In semantic variant primary progressive aphasia (svPPA), TDP-43 pathology follows a four-stage progression, initiating in the temporal regions and amygdala before extending to other cortical areas [188,189,190]. This pattern of spread provides insights into the progressive nature of language deficits observed in svPPA patients. Behavioral variant frontotemporal dementia (bvFTD) exhibits a distinct pattern of TDP-43 pathology progression. Beginning in the orbital and rectal gyri, it subsequently involves frontal, temporal, and subcortical structures before affecting motor areas and, ultimately, the visual cortex [188,189,190]. This progression aligns with the evolving behavioral and cognitive symptoms characteristic of bvFTD. In cases where FTLD overlaps with motor neuron disease (FTLD-MND), TDP-43 pathology manifests as symmetric atrophy in medial temporal and prefrontal regions, coupled with asymmetric atrophy in dorsal cortical and subcortical areas [188,189,190]. This pattern may explain the combination of cognitive, behavioral, and motor symptoms observed in these patients.

The coexistence of granulovacuolar degeneration (GVD) with TDP-43 lesions in the hippocampus of FTLD patients has garnered attention [191]. The presence of necrosome-positive GVD, featuring phosphorylated forms of RIPK1, RIPK3, and MLKL, suggests a potential link between TDP-43 pathology and necroptotic cell death mechanisms in affected neurons.

Genetic factors play a crucial role in FTLD pathogenesis, with mutations in several genes linked to TDP-43 proteinopathy. Progranulin (PGRN) gene mutations, associated with familial FTLD-U, influence TDP-43 processing and may contribute to the generation of pathological TDP-43 fragments [192]. Additionally, variations in TMEM106B, GRN, and C9orf72 genes have been implicated in FTLD cases exhibiting cytoplasmic TDP-43 deposition [193].

Understanding the stage-specific progression of TDP-43 pathology in different FTLD syndromes provides valuable insights into disease mechanisms and potential targets for therapeutic intervention. As research progresses, elucidating the interplay between TDP-43 and other molecular players in FTLD may pave the way for more targeted and effective treatment strategies for this devastating group of neurodegenerative disorders.

Alzheimer’s disease (AD)

AD stands as the foremost cause of cognitive decline in the elderly population, characterized by progressive neurodegeneration and distinct neuropathological features [194,195,196]. While traditionally defined by the accumulation of β-amyloid plaques and tau neurofibrillary tangles, recent research has highlighted the significant role of TDP-43 proteinopathy in AD pathogenesis [197]. The involvement of TDP-43 in AD appears to be multifaceted, potentially influencing disease progression through both Aβ-dependent and independent mechanisms. TDP-43 pathology in AD follows a distinct anatomical progression. The pathological changes initiate in the amygdala before spreading to the entorhinal cortex and subiculum. Subsequently, the pathology affects the dentate gyrus of the hippocampus and occipitotemporal cortex. As the disease advances, it extends to the insular cortex, ventral striatum, basal forebrain, and inferior temporal cortex. The progression continues, involving the substantia nigra, inferior olive, and midbrain tectum. In its most advanced form, the pathology reaches the basal ganglia and middle frontal cortex. This pattern of progression demonstrates the gradual and widespread impact of TDP-43 pathology across various brain regions in AD, from its initial focal point to its eventual extensive distribution [198]. This staged pattern of TDP-43 distribution provides insights into the evolving nature of cognitive and behavioral symptoms observed in AD patients. The co-existence of TDP-43 pathology with Aβ and tau aggregates correlates with more severe cognitive impairment in AD [127]. This synergistic effect suggests that TDP-43 may exacerbate the neurodegenerative process. The predilection of TDP-43 pathology for the hippocampus in AD may explain the prominence of memory deficits in affected individuals [199]. Hippocampal atrophy shows a positive correlation with TDP-43 deposition and neurofibrillary tangle burden, while exhibiting an inverse relationship with age [200, 201]. This observation highlights the complex interplay between various pathological processes and aging in AD progression.

Interestingly, the clinical significance of TDP-43 pathology in AD appears to be dependent on its anatomical extent. TDP-43 aggregates confined to the amygdala may not substantially increase the likelihood of clinical AD-type dementia, whereas more widespread TDP-43 pathology is associated with a higher risk of cognitive impairment [201]. Genetic studies have implicated specific TARDBP gene mutations, such as p.A90V, in increasing AD risk [202]. These findings suggest that alterations in TDP-43 function, even in the absence of overt aggregation, may contribute to AD pathogenesis. Understanding the mechanisms by which TDP-43 interacts with other pathological proteins and contributes to neuronal dysfunction may lead to novel strategies for early diagnosis and treatment of AD. Future investigations may focus on elucidating the molecular pathways through which TDP-43 influences AD progression, exploring potential biomarkers based on TDP-43 pathology, and developing targeted therapies to mitigate the detrimental effects of TDP-43 dysfunction in AD.

Perry syndrome

Perry syndrome represents a unique form of neurodegenerative disorder characterized by its autosomal dominant inheritance pattern and distinctive clinical presentation [203, 204]. The clinical spectrum of Perry syndrome encompasses rapidly progressive atypical parkinsonism, psychiatric disturbances, weight loss, and central hypoventilation. This multifaceted presentation underscores the complex nature of the disorder and its impact on various neurological systems. Neuropathologically, Perry syndrome is distinguished by the presence of TDP-43 inclusions across diverse cellular compartments [205,206,207,208]. These aggregates manifest in neuronal soma, oligodendroglial cytoplasm, neuronal nuclei, perivascular astrocytic processes, and abnormal neuritic structures. The basal ganglia, particularly the substantia nigra and globus pallidus, exhibit the highest density of TDP-43 pathology [207]. This observation suggests a complex interplay between dynactin dysfunction and TDP-43 pathology in the disease process. The relationship between dynactin abnormalities and TDP-43 aggregation in Perry syndrome may involve alterations in dense core vesicle kinetics, synaptic function, and microtubule interactions [209]. These perturbations could lead to deficits in neurotransmission and axonal transport, potentially disrupting normal TDP-43 trafficking and contributing to its pathological accumulation.

Understanding the molecular mechanisms underlying the connection between dynactin dysfunction and TDP-43 pathology in Perry syndrome represents a crucial area for future research. Elucidating these pathways may not only enhance our comprehension of this rare disorder but also provide insights into broader neurodegenerative processes involving TDP-43.

Huntington’s disease (HD)

HD is a progressive neurodegenerative disorder characterized by its autosomal dominant inheritance pattern and a distinctive genetic etiology involving the expansion of CAG repeats in the Huntingtin (Htt) gene [210]. This genetic abnormality leads to a complex clinical presentation, encompassing cognitive decline, motor dysfunction, and psychiatric disturbances. The neuropathological landscape of HD is marked by the presence of protein aggregates in specific brain regions, particularly subcortical structures [211, 212]. These inclusions contain not only mutant huntingtin but also TDP-43, suggesting a potential interplay between these proteins in disease pathogenesis. Interestingly, the co-localization of TDP-43 and huntingtin is observed in neuritic processes and glial cytoplasmic aggregates, but not in intranuclear inclusions [213]. HD pathology is further complicated by the presence of additional protein aggregates, including tau and α-synuclein [214]. The temporal sequence of protein accumulation in HD has been elucidated, with huntingtin deposition preceding the appearance of phosphorylated TDP-43. This chronological pattern provides insights into the potential cascade of molecular events leading to neuronal dysfunction in HD. Cellular models expressing mutant huntingtin with expanded polyglutamine repeats have demonstrated the induction of TDP-43 aggregation [215]. This observation suggests a direct link between the primary genetic defect in HD and TDP-43 pathology. Moreover, the modulation of huntingtin aggregation has been shown to influence TDP-43 aggregation [216], further supporting the interconnected nature of these pathological processes.

Studies in model organisms have provided valuable insights into the role of TDP-43 in HD pathogenesis. In C. elegans, the absence of TDP-43 orthologs ameliorates behavioral and neurodegenerative phenotypes associated with expanded polyglutamine expression [217]. This finding implies that TDP-43 may contribute to the toxic effects of mutant huntingtin, potentially exacerbating disease progression. The involvement of progranulin in modulating polyglutamine toxicity has emerged as an intriguing avenue for therapeutic exploration [217]. This protein’s ability to influence disease processes in both invertebrate and mammalian models highlights its potential as a target for intervention in HD. These collective findings underscore the complex molecular interactions underlying HD pathogenesis, extending beyond the primary genetic defect to involve multiple protein aggregation processes. The interplay between huntingtin, TDP-43, and other proteins in HD presents both challenges and opportunities for developing targeted therapeutic strategies.

Limbic-predominant age-related TDP-43 encephalopathy (LATE)

LATE represents a newly recognized form of neurodegenerative disorder, primarily affecting the elderly population [218]. This condition is characterized by the accumulation of TDP-43 protein in specific brain regions, with or without accompanying hippocampal sclerosis [218, 219]. The neuropathological progression of LATE follows a distinct anatomical pattern, initiating in the amygdala before extending to the entorhinal cortex and subiculum. As it advances, the dentate gyrus and occipitotemporal cortex become involved, followed by the insular cortex, ventral striatum, basal forebrain, and inferior temporal cortex. In later phases, the substantia nigra, inferior olive, and midbrain tectum are also impacted. Ultimately, the basal ganglia and middle frontal cortex succumb to this gradual pathological progression [213, 218, 220, 221]. This staged progression provides insights into the evolving nature of cognitive and behavioral symptoms observed in affected individuals. The nosological status of LATE remains a topic of debate within the scientific community [222]. Some researchers consider it a distinct entity, while others view it as part of a broader spectrum of TDP-43-associated neurodegenerative diseases. This ongoing discussion highlights the complexities in categorizing age-related neurodegenerative disorders.

Genetic studies have identified several risk alleles associated with LATE neuropathological change (LATE-NC), including variations in GRN, TMEM106B, ABCC9, KCNMB2, and APOE genes [220, 223, 224]. The partial overlap of genetic risk factors between LATE and other neurodegenerative conditions, such as frontotemporal lobar degeneration and AD, suggests shared pathogenetic mechanisms while also pointing to distinct pathways. Epidemiological investigations have revealed interesting patterns in LATE-NC distribution. The limbic/neocortical variant appears to be more common in female populations [224]. Notably, no significant racial differences have been observed in either the clinical manifestation or pathological distribution of LATE-NC [225]. Age emerges as the most significant risk factor for LATE-NC, with a particularly high prevalence in individuals over 80 years old [220]. This age-dependent increase in prevalence underscores the importance of considering LATE in the differential diagnosis of cognitive decline in the elderly.

Future research directions may include developing biomarkers for early detection of LATE-NC, investigating potential therapeutic interventions targeting TDP-43 aggregation, and exploring the interaction between LATE and other age-related neurodegenerative processes. As our understanding of LATE evolves, it may lead to more personalized approaches to managing cognitive decline in the elderly population.

Hippocampal sclerosis (HS)

HS represents a distinctive neuropathological entity characterized by severe neuronal loss and gliosis in specific regions of the hippocampus, notably the CA1 subfield and/or subiculum [226, 227]. This condition exhibits an age-dependent prevalence, with a markedly higher occurrence in the oldest-old population. A recent study found that HS was present in 23.4% of individuals with chronic traumatic encephalopathy (CTE), a neurodegenerative condition associated with repetitive head impacts [228].

A striking feature of HS is its frequent co-occurrence with TDP-43 pathology, observed in a substantial majority of cases [227]. This association suggests a potential interplay between these two pathological processes in the aging brain. In fact, TDP-43 inclusions were present in 43.3% of individuals with CTE, indicating a strong relationship between these pathologies [228]. The distribution of TDP-43 inclusions follows a distinct pattern that can be categorized into three phases. The initial phase, observed in nearly half (43.7%) of patients, primarily affects the amygdala. In the subsequent phase, seen in 40% of cases, the pathology extends to encompass the hippocampus or entorhinal cortex. The final and most extensive phase, present in a smaller subset of patients (16.3%), is characterized by additional TDP-43 pathology spreading to the temporal and frontal cortices [221].

The synergistic effect of HS and TDP-43 pathology on cognitive function has been documented across multiple domains [227]. This observation underscores the complex nature of age-related cognitive decline and the potential contribution of multiple pathological processes. A study by Gauthreaux et al. found that among participants with LATE-NC, those with comorbid HS tended to have worse cognitive status and scored lower on the Personal Care and Orientation domains of the Clinical Dementia Rating scale [229]. The debate surrounding the classification of HS as a primary neurodegenerative process or a secondary phenomenon remains unresolved [199]. The lack of definitive evidence establishing a causal link between TDP-43 proteinopathy and HS further complicates this issue, highlighting the need for additional research in this area. Genetic factors, particularly the APOE ε4 allele, have been implicated in modulating TDP-43 aggregation in the context of HS [230]. This finding suggests a potential interaction between genetic risk factors and protein aggregation processes in the aging brain. However, Gauthreaux et al. found no significant differences in APOE ε4 carrier status between LATE-NC participants with and without HS, indicating that the relationship between genetic factors and HS may be complex [229]. The coexistence of TDP-43 and tau pathology in aged hippocampi, each contributing independently to cognitive impairment, adds another layer of complexity to the neuropathological landscape of HS [200]. This observation emphasizes the multifactorial nature of age-related cognitive decline and the challenges in attributing clinical symptoms to specific pathological entities. The emergence of the term “cerebral age-related TDP-43 with sclerosis” (CARTS) reflects an evolving understanding of the interrelationship between HS, TDP-43 pathology, and cerebrovascular changes in the aging brain [200, 231, 232]. This concept highlights the need for a more integrated approach to studying age-related neuropathological changes.

Niemann-Pick C disease (NP-C)

NP-C represents a unique form of lysosomal storage disorder, characterized by its multisystemic impact and distinctive neurological manifestations [233]. This rare genetic condition, primarily caused by mutations in the NPC1 or NPC2 genes, presents with a complex array of symptoms, including the pathognomonic vertical supranuclear gaze palsy. Recent investigations have unveiled an intriguing connection between NP-C and TDP-43 pathology, with the latter being observed in the cerebellar dentate nucleus of affected individuals [234]. This finding adds a new dimension to our understanding of NP-C pathogenesis and suggests potential overlap with other neurodegenerative disorders involving TDP-43 dysfunction. Liu et al. further reported that TDP-43 proteinopathy occurs independently of autophagic substrate accumulation in NP-C, underlying nuclear defects [235]. The accumulation of proteins associated with neurodegenerative diseases, including hyperphosphorylated tau, α-synuclein, and TDP-43, has been observed in NP-C [235,236,237]. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing protein synthesis, folding, maintenance, and degradation. The mechanisms underlying TDP-43 pathology in NP-C remain to be fully elucidated. However, current hypotheses point towards the involvement of lysosomal dysfunction and aberrant RNA processing. The cellular response to oxidative stress appears to play a crucial role, triggering the relocalization of TDP-43 to stress granules and lysosomes, thereby disrupting its normal nuclear-cytoplasmic distribution. Molecular studies have identified several genes whose expression is altered in NP-C and are known to be regulated by TDP-43 at the RNA processing level [234]. This observation highlights the far-reaching consequences of TDP-43 dysfunction on cellular homeostasis and gene expression patterns. Therapeutic explorations in NP-C have yielded promising results, with antioxidants like N-acetyl-cysteine (NAC) and the cholesterol-sequestering agent 2-hydroxypropyl-β-cyclodextrin (CD) demonstrating potential in restoring TDP-43 nuclear localization [234]. These findings open new avenues for targeted interventions in NP-C and potentially other TDP-43-related disorders.

Alexander disease (AxD)

AxD represents a unique form of neurodegenerative disorder, characterized by its genetic etiology involving mutations in the glial fibrillary acidic protein (GFAP) gene [238, 239]. This rare condition highlights the critical role of astrocyte dysfunction in neurological pathogenesis. The hallmark of AxD is the presence of Rosenthal fibers (RFs), eosinophilic inclusions primarily composed of GFAP, within astrocytes. Investigations have revealed an intriguing association between these characteristic inclusions and TDP-43 pathology, adding a new dimension to our understanding of AxD pathogenesis [239]. In contrast to other TDP-43 proteinopathies, AxD exhibits a unique pattern of TDP-43 aggregation. Full-length phosphorylated TDP-43 predominates in AxD, rather than the cleaved fragments typically observed in conditions such as ALS and FTLD. This distinct post-translational profile suggests that the mechanisms underlying TDP-43 pathology in AxD may differ from those in other neurodegenerative disorders [239]. Animal models of AxD, including GfapR236H/+ knock-in mice and transgenic mice overexpressing human wild-type GFAP, have provided valuable insights into the relationship between GFAP accumulation and TDP-43 pathology. The colocalization of TDP-43 with RFs in these models suggests a potential interaction between GFAP aggregation and TDP-43 dysfunction [239]. Interestingly, the formation of RFs in these animal models occurs independently of increased TDP-43 levels, indicating that TDP-43 deposition may be a consequence rather than a cause of RF formation. This observation has led to the hypothesis that TDP-43 pathology in AxD may result from glial cell injury caused by excessive GFAP accumulation [239].

A proposed pathogenic mechanism for TDP-43 involvement in AxD suggests a cascade of events initiated by abnormal GFAP deposition. This leads to glial cell stress, followed by TDP-43 deposition in RFs, potentially influenced by inflammatory processes [238, 239]. Given TDP-43’s crucial role in RNA processing and gene regulation, its sequestration in RFs may further exacerbate GFAP pathology through altered splicing mechanisms [240, 241]. However, the extrapolation of these findings to human AxD patients remains challenging due to limitations in pathological detection of TDP-43 in mouse models. This underscores the need for further research using human tissue samples and more advanced experimental models.

10 Multiple system atrophy(MSA)

MSA presents a unique challenge in the realm of neurodegenerative disorders, characterized by its distinctive α-synuclein-positive oligodendroglial inclusions [242]. This pathological hallmark is associated with widespread neuronal loss and gliosis, contributing to the complex clinical presentation of MSA [243]. Recent investigations have unveiled an intriguing, albeit infrequent, association between MSA and TDP-43 pathology [244, 245]. This co-occurrence, observed in approximately 7% of MSA cases, adds a new layer of complexity to our understanding of the disease’s neuropathological landscape.

The distribution of TDP-43 pathology in MSA exhibits a predilection for specific brain regions, with the medial temporal lobe structures, particularly the amygdala and hippocampus, showing heightened vulnerability [244, 245]. This spatial pattern suggests a potential interaction between regional susceptibility factors and TDP-43 aggregation processes. The morphological spectrum of TDP-43 pathology in MSA is diverse, encompassing subpial astrocytic inclusions, neuronal inclusions, dystrophic neurites, perivascular deposits, and glial cytoplasmic inclusions (GCIs) [244]. This variety of pathological manifestations reflects the multifaceted nature of protein aggregation in neurodegenerative disorders. Several risk factors have been identified for the development of TDP-43 pathology in MSA, including advanced age, concomitant AD pathology, argyrophilic grain disease, and hippocampal sclerosis [243]. Notably, advanced age emerges as an independent risk factor, underscoring the complex interplay between aging and protein aggregation processes.

A recent case report adds to this growing body of evidence, describing a patient with pathologically confirmed MSA-P who exhibited widespread α-synuclein GCIs with colocalization of TDP-43 within both the paracentral cortex and lenticular nucleus. This case, along with two previously reported instances, demonstrates that TDP-43 and α-synuclein can coexist in GCIs in MSA, suggesting a possible interaction between the two pathologies [246]. The observation of TDP-43 and α-synuclein co-deposition in specific brain regions of MSA patients, such as the mammillothalamic tract and thalamic fasciculus, raises intriguing questions about potential protein-protein interactions in disease pathogenesis [244]. This finding suggests that cross-seeding or shared aggregation mechanisms may contribute to the complex neuropathology of MSA.

Despite these neuropathological observations, genetic analyses have not revealed direct links between TDP-43 pathology and mutations in the α-synuclein-encoding SNCA gene or variants in TMEM106B or GRN [244]. This lack of genetic association suggests that the presence of TDP-43 pathology in MSA may be driven by alternative mechanisms or represent a secondary phenomenon.

The limited distribution and relatively low frequency of TDP-43 pathology in MSA indicate that it is unlikely to be a primary driver of the disease process. However, its presence may contribute to the heterogeneity of clinical presentations and potentially influence disease progression in affected individuals.

11 progressive supranuclear palsy (PSP)

PSP represents a distinct neurodegenerative disorder with a complex neuropathological profile. Recent investigations have revealed an intriguing, albeit infrequent, association with TDP-43 pathology, observed in approximately 7% of PSP cases [247]. This finding adds a new dimension to our understanding of PSP’s molecular underpinnings.

TDP-43 pathology in PSP progresses through five stages, starting in the amygdala, then spreading to the hippocampus and entorhinal cortex, followed by concurrent involvement of these areas, then extending to the medial occipitotemporal gyrus, and finally reaching the dorsolateral frontal lobe. Stage 3 is most common. TDP-43 abnormalities often coexist with other neuropathological changes in PSP. Patients with TDP-43 pathology exhibit more severe tau accumulation in limbic regions and a higher incidence of hippocampal sclerosis compared to those without [248, 249]. This observation suggests potential synergistic effects between different protein aggregation processes in driving neurodegeneration.

12 corticobasal degeneration(CBD)

CBD represents a complex neurodegenerative disorder characterized by the accumulation of 4R tau protein in various cerebral regions. This condition is intricately linked to the clinical manifestation of corticobasal syndrome (CBS), an atypical form of parkinsonism with diverse presentations [250]. Investigations have unveiled an intriguing association between CBD and TDP-43 pathology, observed in approximately 15.4% of CBD cases [251]. Recent research has shown that TDP-43 pathology is more prevalent in CBD than previously thought, with one study reporting TDP-43 inclusions in 90% of examined cases [252]. The spatial distribution of TDP-43 pathology in CBD exhibits a predilection for specific brain regions, with the midbrain tegmentum and subthalamic nucleus being the most commonly affected areas. This pattern of regional vulnerability suggests potential interactions between TDP-43 and the underlying tau pathology characteristic of CBD. A classification system has been developed to categorize CBD cases based on the extent of TDP-43 pathology, distinguishing between TDP-limited (52%) and TDP-severe (48%) subtypes [253]. This stratification provides insights into the heterogeneity of CBD and its potential clinical implications. A significant finding is the topographical correlation between neuronal cytoplasmic aggregation of TDP-43 and neuronal loss in CBD. Sainouchi et al. demonstrated that the appearance of TDP-43 neuronal cytoplasmic inclusions (NCIs) was significantly correlated with neuronal loss in multiple brain regions, including subcortical grey matter and midbrain [252]. This suggests that TDP-43 protein aberration might be directly associated with neuronal degeneration in CBD. The presence of severe TDP-43 pathology, particularly affecting the midbrain tectum, has been associated with downward gaze palsy, a clinical feature typically associated with PSP. This overlap in clinical presentation highlights the challenges in differential diagnosis between CBD and PSP, especially in cases with significant TDP-43 involvement [253]. CBD cases with TDP-43 pathology demonstrate a higher burden of tau pathology in the olivopontocerebellar system compared to TDP-43-negative cases. This observation suggests a potential synergistic effect between TDP-43 and tau aggregation processes in driving neurodegeneration in specific brain regions [253].

The impact of TDP-43 inclusions varies among cell types. NCIs showed the strongest correlation with neuronal loss, while the impact of glial inclusions (astrocytic and oligodendroglial) appeared to be less significant [252].

The distinct clinicopathological features of CBD cases with severe TDP-43 pathology have led to the proposal of a new subtype, termed “CBD-OPCA” (olivopontocerebellar atrophy). This variant is characterized by the presence of TDP-43 immunoreactive neurons and glial cytoplasmic inclusions in both the basal ganglia and olivopontocerebellar system [254]. The similarities observed between CBD-TDP and PSP-TDP cases suggest shared pathogenic mechanisms, with TDP-43 potentially playing a modulatory role through co-deposition with other pathological proteins. This overlap underscores the complex interplay between various protein aggregation processes in neurodegenerative disorders.

As research in this field progresses, future investigations may focus on elucidating the molecular mechanisms underlying the selective vulnerability of certain brain regions to TDP-43 pathology in CBD, exploring potential cross-talk between tau and TDP-43 aggregation processes, and developing targeted therapeutic strategies that address the complex proteinopathy landscape of CBD and related disorders.

Discussion

TDP-43 as a multifunctional genome guardian: from DNA binding to chromatin remodeling

TDP-43’s involvement in DNA interactions and chromatin dynamics reveals its role as a multifunctional genome guardian. This protein exhibits high affinity for single-stranded DNA (ssDNA) TG repeats and interacts with double-stranded DNA (dsDNA), particularly at free dsDNA termini. These DNA-binding capabilities underpin TDP-43’s diverse functions in transcriptional regulation, acting as both a repressor and an activator in a context-dependent manner. The repressive function of TDP-43 is exemplified by its interaction with the mouse Acrv1 gene promoter, where it binds to GTGTGT motifs and recruits the gene to the nuclear matrix, physically sequestering it from transcriptional machinery. Conversely, TDP-43 can activate gene expression, as seen in its cooperation with NF-κB to enhance TNF-alpha expression in response to LPS stimulation in human monocytic cells. TDP-43’s interaction with chromatin remodeling complexes, particularly the SWI/SNF complex, adds another layer to its regulatory capabilities. By interfering with the recruitment of chromatin remodelers like Chd1 to specific loci, TDP-43 can modulate nucleosome dynamics and gene accessibility. This function is critically important for stress-responsive genes, linking TDP-43’s chromatin-related activities to cellular stress responses. Furthermore, TDP-43’s role in maintaining R-loop homeostasis connects its DNA-binding properties with its RNA-processing functions. By resolving these DNA-RNA hybrid structures, TDP-43 prevents genomic instability, a common feature in neurodegenerative diseases. The discovery of TDP-43’s involvement in retrotransposon silencing further exemplifies its genome-protective functions, contributing to the maintenance of genomic stability by directly binding to retrotransposon-derived RNAs and recruiting nuclear RNA degradation complexes.

In summary, TDP-43’s DNA-related functions position it as a crucial guardian of genomic integrity and transcriptional fidelity. Its ability to bind DNA, modulate chromatin structure, regulate R-loops, and silence retrotransposons collectively contribute to maintaining cellular homeostasis and preventing genomic instability. This multifaceted role in genome protection provides a foundation for understanding how TDP-43 dysfunction can lead to the widespread cellular abnormalities observed in neurodegenerative diseases.

TDP-43: the master orchestrator of RNA metabolism

TDP-43 emerges as a master orchestrator of RNA metabolism, with its functions spanning from alternative splicing regulation to mRNA stability control and beyond. At the core of these functions is TDP-43’s ability to recognize specific RNA sequences, particularly UG-rich regions, through its RNA recognition motifs (RRMs). In alternative splicing, TDP-43 exhibits remarkable versatility, promoting exon skipping, altering splice site selection, and regulating mutually exclusive exons. The discovery of its role in cryptic exon repression has provided a crucial link between splicing dysregulation and disease pathogenesis. TDP-43 suppresses the inclusion of cryptic exons in genes like STMN2, UNC13A, and SORT1, with the loss of this repression in TDP-43 proteinopathies leading to the production of aberrant transcripts and potentially toxic protein isoforms. TDP-43’s influence extends to mRNA stability regulation, where it can either promote or inhibit mRNA decay by binding to the 3’ UTRs of target mRNAs. This differential regulation allows TDP-43 to fine-tune gene expression levels post-transcriptionally, affecting cellular processes ranging from cell cycle control to stress response. For instance, TDP-43 stabilizes G3BP1 mRNA, a key component of stress granules, while promoting the instability of CDK6 mRNA. The protein’s involvement in miRNA biogenesis adds another dimension to its RNA regulatory functions. TDP-43 participates in both canonical and non-canonical miRNA production pathways, indirectly influencing the expression of numerous genes through miRNA-mediated silencing. This function creates a complex regulatory network where TDP-43 can modulate gene expression at multiple levels simultaneously. TDP-43’s role in stress granule dynamics bridges its RNA-related functions with cellular stress responses. By regulating the formation and dissolution of stress granules, TDP-43 influences mRNA triage during stress conditions, a function particularly relevant in the context of neurodegenerative diseases. The emerging role of TDP-43 in circular RNA (circRNA) biogenesis further expands its influence on the RNA regulatory landscape, potentially providing new biomarkers for TDP-43-related disorders.

In summary, TDP-43 stands as a central figure in the complex world of RNA metabolism. Its multifaceted roles in splicing regulation, mRNA stability control, miRNA biogenesis, stress granule dynamics, and circRNA production collectively position TDP-43 as a key orchestrator of post-transcriptional gene regulation. This intricate involvement in RNA processing underlies the widespread cellular dysfunction observed when TDP-43’s function is compromised in neurodegenerative diseases.

TDP-43 pathology in neurodegenerative diseases: a unifying mechanism with diverse manifestations

TDP-43 pathology emerges as a unifying feature across a spectrum of neurodegenerative diseases, each with distinct clinical presentations. The varied anatomical progression patterns of TDP-43 aggregation in different disorders provide crucial insights into the relationship between molecular pathology and clinical symptomatology.

In ALS and FTLD, the core TDP-43 proteinopathies, TDP-43 pathology exhibits disease-specific progression patterns. These patterns correlate closely with the characteristic symptoms of each disorder, such as motor deficits in ALS and language or behavioral changes in FTLD. The discovery of TDP-43 pathology in other neurodegenerative conditions, including Alzheimer’s disease, Huntington’s disease, and even some cases of Parkinson’s disease, suggests a broader role for TDP-43 dysfunction in neurodegeneration. The common thread across these diverse conditions is the disruption of TDP-43’s normal nuclear functions, particularly in RNA processing. This disruption leads to widespread cellular dysfunction through multiple mechanisms: (1) Splicing dysregulation: The loss of nuclear TDP-43 results in aberrant splicing events, including the inclusion of cryptic exons in key neuronal genes. This dysregulation affects critical cellular processes such as axonal maintenance, synaptic function, and neuronal survival. (2) Altered stress response: TDP-43’s role in stress granule dynamics suggests that its dysfunction may impair the cellular stress response, a common feature across neurodegenerative diseases. (3) Potential gain of toxic function: Cytoplasmic aggregation of TDP-43 may not only lead to loss of normal function but also gain of toxic properties, possibly through sequestration of other essential proteins or RNAs. (4) Prion-like propagation: The spreading pattern of TDP-43 pathology in different diseases suggests a potential prion-like propagation mechanism, which could explain the progressive nature of these disorders.

The presence of TDP-43 pathology alongside other disease-specific protein aggregates (e.g., tau in AD, huntingtin in HD) raises intriguing questions about the interplay between different pathological processes. This co-occurrence may explain the clinical heterogeneity observed within each disease and the overlapping symptoms across different neurodegenerative conditions.

Understanding the common and distinct features of TDP-43 pathology across various neurodegenerative diseases is crucial for several reasons: (1) It provides a potential explanation for the clinical variability observed within and between different neurodegenerative conditions.

(2) It suggests that targeting TDP-43 dysfunction could have therapeutic potential across multiple disorders. (3) It highlights the importance of considering TDP-43 pathology in the diagnosis and prognosis of neurodegenerative diseases, potentially leading to more accurate disease classification and personalized treatment approaches.

In summary, the ubiquity of TDP-43 pathology across various neurodegenerative diseases underscores its fundamental role in maintaining neuronal health. The diverse manifestations of TDP-43 dysfunction in different disorders reflect the complexity of its cellular functions and the vulnerability of specific neuronal populations. Future research should focus on unraveling the mechanisms that drive the disease-specific patterns of TDP-43 pathology and exploring how these insights can be translated into targeted therapeutic strategies.

Conclusion

This comprehensive review unveils the multifaceted nature of TDP-43, revealing its pivotal role not only in RNA metabolism but also in DNA interactions, chromatin dynamics, and cellular energetics. The discovery of cryptic exon inclusion as a hallmark of TDP-43 dysfunction provides a crucial link between molecular pathology and neurodegenerative phenotypes. Our analysis of TDP-43’s involvement across various neurodegenerative disorders and cancers highlights its context-dependent functions, challenging traditional disease boundaries. The elucidation of TDP-43’s impact on glial cells and mitochondrial function emphasizes the need for a holistic approach to understanding and treating TDP-43-related pathologies. These insights collectively reshape our understanding of TDP-43 biology, offering new perspectives on disease mechanisms and opening novel avenues for diagnostic and therapeutic interventions. By bridging molecular mechanisms with clinical manifestations, this study sets the stage for innovative approaches in neurodegenerative research, potentially leading to more effective strategies for early diagnosis and targeted treatments.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

AD:: Alzheimer’s Disease
ALS:: Amyotrophic Lateral Sclerosis
APA:: Alternative Polyadenylation
ASO:: Antisense Oligonucleotide
AxD:: Alexander Disease
bvFTD:: Behavioral Variant Frontotemporal Dementia
CARTS:: Cerebral Age-Related TDP-43 with Sclerosis
CBD:: Corticobasal Degeneration
CE:: Cryptic Exon
circRNA:: Circular RNA
CTE:: Chronic Traumatic Encephalopathy
CTD:: C-Terminal Domain
FTLD:: Frontotemporal Lobar Degeneration
fALS:: Familial Amyotrophic Lateral Sclerosis
FUS:: Fused in Sarcoma
GCI:: Glial Cytoplasmic Inclusion
GVD:: Granulovacuolar Degeneration
HD:: Huntington’s Disease
HDAC:: Histone Deacetylase
HS:: Hippocampal Sclerosis
LATE:: Limbic-Predominant Age-Related TDP-43 Encephalopathy
LATE-NC:: LATE Neuropathological Change
lncRNA:: Long Non-Coding RNA
miRNA:: MicroRNA
MSA:: Multiple System Atrophy
NCI:: Neuronal Cytoplasmic Inclusion
NLS:: Nuclear Localization Signal
NP-C:: Niemann-Pick C Disease
NTD:: N-Terminal Domain
OPCA:: Olivopontocerebellar Atrophy
PSP:: Progressive Supranuclear Palsy
PTM:: Post-Translational Modification
RBP:: RNA-Binding Protein
RF:: Rosenthal Fiber
ROS:: Reactive Oxygen Species
RRM:: RNA Recognition Motif
sALS:: Sporadic Amyotrophic Lateral Sclerosis
svPPA:: Semantic Variant Primary Progressive Aphasia
TDP-43:: TAR DNA-Binding Protein 43

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2024 High-quality Development Research Project of Shenzhen Bao’an Public Hospital, Shenzhen, No. YNXM2024015.

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Jixiang Zeng and Chunmei Luo contributed equally to this work as co-first authors.

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Shenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guang Dong, 518000, China
Jixiang Zeng, Chunmei Luo, Yang Jiang, Tao Hu, Bixia Lin, Yuanfang Xie, Jiao Lan & Jifei Miao

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Jixiang Zeng
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Chunmei Luo
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Yang Jiang
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Tao Hu
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Bixia Lin
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Yuanfang Xie
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Jiao Lan
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Jixiang Zeng and Chunmei Luo contributed equally to this work as co-first authors. They were responsible for extensive literature review, manuscript drafting, and critical analysis of existing research. Yang Jiang, Tao Hu, Bixia Lin, and Yuanfang Xie contributed to specific sections of the review, providing additional literature insights and helping with manuscript revision. Jiao Lan and Jifei Miao conceived the idea for the review, guided the overall structure and content, and provided critical revisions for important intellectual content.

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Zeng, J., Luo, C., Jiang, Y. et al. Decoding TDP-43: the molecular chameleon of neurodegenerative diseases. acta neuropathol commun 12, 205 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40478-024-01914-9

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Received: 22 September 2024
Accepted: 13 December 2024
Published: 31 December 2024
DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40478-024-01914-9

Decoding TDP-43: the molecular chameleon of neurodegenerative diseases

Abstract

Introduction

History of TDP-43

Physiological functions of TDP-43

Role of TDP-43 in DNA interactions and chromatin dynamics

TDP-43’s involvement in chromatin silencing and transcriptional regulation

TDP-43’s role in histone modifications and chromatin remodeling complexes

TDP-43’s influence on dna methylation and transcriptional machinery

Role of TDP-43 in RNA metabolism

TDP-43 interactome and splicing regulation

Cryptic exon inclusion and TDP-43 dysfunction

Circular RNAs and TDP-43 splicing dysregulation

TDP-43 and miRNA regulation

TDP-43 in disease

The multifaceted pathogenesis of TDP-43

The intricate regulatory role of TDP-43 in cancer

TDP-43 in neurodegenetive disease

Amyotrophic lateral sclerosis (ALS)

Frontotemporal lobar degeneration (FTLD)

Alzheimer’s disease (AD)

Perry syndrome

Huntington’s disease (HD)

Limbic-predominant age-related TDP-43 encephalopathy (LATE)

Hippocampal sclerosis (HS)

Niemann-Pick C disease (NP-C)

Alexander disease (AxD)

10 Multiple system atrophy(MSA)

11 progressive supranuclear palsy (PSP)

12 corticobasal degeneration(CBD)

Discussion

TDP-43 as a multifunctional genome guardian: from DNA binding to chromatin remodeling

TDP-43: the master orchestrator of RNA metabolism

TDP-43 pathology in neurodegenerative diseases: a unifying mechanism with diverse manifestations

Conclusion

Data availability

Abbreviations

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding authors

Ethics declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Additional information

Publisher’s note

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About this article

Cite this article

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Keywords

Acta Neuropathologica Communications

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