| 2021 |
Cryo-EM structural determination of pathological TDP-43 filaments from ALS with FTLD brain revealed an amyloid-like filament comprising a single protofilament with a double-spiral-shaped fold spanning residues 282-360 in the low-complexity domain, showing no similarity to TDP-43 filaments formed in vitro and lacking classical cross-β amyloid structure. |
Cryo-electron microscopy of brain-derived TDP-43 aggregates |
Nature |
High |
34880495
|
| 2019 |
RNA binding antagonizes neurotoxic phase transitions of TDP-43: aberrant interactions between low-complexity domains drive pathological inclusion formation, and this process is antagonized by RNA binding. Pathological inclusions can form outside stress granules. Treatment with oligonucleotides composed of TDP-43 target sequences prevents inclusions and rescues neurotoxicity. |
Optogenetic induction of TDP-43 proteinopathy in live cells with spatiotemporal control, live-cell imaging, neurotoxicity assays |
Neuron |
High |
30826182
|
| 2016 |
TDP-43 accumulates in neuronal mitochondria in ALS/FTD. In mitochondria, wild-type and mutant TDP-43 preferentially bind mitochondria-transcribed mRNAs encoding respiratory complex I subunits ND3 and ND6, impairing their expression and causing specific complex I disassembly. Suppression of TDP-43 mitochondrial localization abolishes mitochondrial dysfunction and neuronal loss, and improves phenotypes in transgenic mutant TDP-43 mice. |
Mitochondrial fractionation, RNA immunoprecipitation, respiratory complex activity assays, transgenic mouse studies with TDP-43 mitochondrial localization signal blocking |
Nature medicine |
High |
27348499
|
| 2020 |
HSP70 family chaperones are the primary components of the liquid core of TDP-43 'anisosomes' (intranuclear liquid spherical shells formed by RNA binding-deficient TDP-43). ATP-dependent HSP70 activity maintains the liquidity of both shells and cores. Reduction of ATP levels converts anisosomes to solid aggregates. Acetylation of RNA recognition motifs renders TDP-43 unable to bind RNA, driving anisosomes formation. |
Live-cell imaging, cryo-electron tomography, mathematical modeling, proteomics (mass spectrometry of anisosomes components), ATP depletion experiments, proteasome inhibition in neurons |
Science |
High |
33335017
|
| 2021 |
TDP-43 condensation capacity (governed by C-terminal domain) is required for efficient assembly on subsets of RNA-binding regions containing long clusters of UG-rich motifs, promoting 'binding-region condensates' via homomeric CTD interactions, and is necessary for regulation of a subset of bound transcripts including TDP-43 mRNA autoregulation. |
Series of TDP-43 CTD variants with graded condensation propensity; in vitro phase separation assays; nuclear mobility (FRAP); iCLIP for RNA-binding regions; RNA-seq for transcriptome regulation |
Cell |
High |
34380047
|
| 2022 |
Casein kinase 1δ-mediated TDP-43 hyperphosphorylation on C-terminal serine residues reduces TDP-43 phase separation and aggregation, rendering condensates more liquid-like and dynamic. Phosphomimetic mutations do not affect nuclear import or RNA regulatory functions but suppress accumulation in membrane-less organelles. Multi-scale molecular dynamics simulations reveal reduced homotypic interactions through enhanced solvation of phosphomimetic residues. |
In vitro phase separation assays with phosphomimetic TDP-43 variants; CK1δ kinase assays; FRAP; molecular dynamics simulations; cellular localization and RNA splicing assays |
The EMBO journal |
High |
35112738
|
| 2025 |
TDP-43 aggregation requires two concurrent events: up-concentration within stress granules beyond a threshold AND oxidative stress. These collectively trigger intra-condensate demixing via RRM1 domain unfolding (enabling intermolecular disulfide bonds) and increased hydrophobic patch interactions in the C-terminal domain, generating a TDP-43-enriched phase within stress granules that transitions to pathological aggregates. TDP-43 variants resistant to intra-condensate demixing eliminate pathological aggregates. |
Live-cell imaging, optogenetic concentration control, iPS-motor neurons, disease mouse model validation, patient sample analysis, engineered TDP-43 variants resistant to demixing |
Cell |
High |
40412392
|
| 2023 |
TDP-43 oligomerization and RNA binding govern TDP-43 stability, splicing functionality, LLPS, and subcellular localization. Oligomerization is modulated by RNA binding. Under impaired proteasomal activity: monomeric TDP-43 forms cytoplasmic inclusions via aggresome-dependent pathway, while RNA binding-deficient TDP-43 aggregates in the nucleus via LLPS-driven pathway. |
Structure-based TDP-43 variants in human neurons and cell lines; near-physiological expression; proteasome inhibition; co-immunoprecipitation; FRAP; imaging |
The EMBO journal |
High |
37431963
|
| 2023 |
Seeding of TDP-43 aggregation requires post-fibrillization proteolytic cleavage to expose the β-sheet-rich amyloid core buried by flanking structured domains in full-length TDP-43 filaments. Only TDP-43 filaments with exposed amyloid core efficiently seeded aggregation of endogenous TDP-43 in cells and enhanced seeding by brain-derived TDP-43 aggregates. |
Recombinant full-length TDP-43 filament production; structural characterization; proteolytic cleavage assays; cell-based seeding assays with brain-derived aggregates |
Nature neuroscience |
High |
37248338
|
| 2019 |
Loss of nuclear TDP-43 is associated with chromatin decondensation around long interspersed nuclear elements (LINEs) and increased LINE1 DNA content. Loss of TDP-43 leads to increased retrotransposition that can be inhibited with antiretroviral drugs. |
Subcellular fractionation, FACS enrichment of TDP-43-negative nuclei from post-mortem FTD-ALS brain, RNA-seq, ATAC-seq for chromatin accessibility, LINE1 retrotransposition assay |
Cell reports |
High |
31042469
|
| 2017 |
TDP-43 suppresses tau expression by promoting mRNA instability through binding to UG repeats in the 3'-UTR of tau mRNA. The C-terminal region of TDP-43 is required for this function. ALS-causing TDP-43 mutations differentially affect tau mRNA instability. |
mRNA stability assays (actinomycin D chase), RNA immunoprecipitation, TDP-43 truncation mutants, in vivo TDP-43(M337V) transgenic mouse analysis, human brain correlation studies |
Nucleic acids research |
High |
28335005
|
| 2021 |
TDP-43 is SUMOylated in the nuclear compartment both covalently (at lysine 136 via SUMO E3 ligase PIAS4, confirmed by SUMO-mutant K136R) and non-covalently in the RRM1 domain at a SUMO-interacting motif (residues 106-110). SUMOylation modifies TDP-43 splicing activity (specifically exon skipping), influences subcellular localization, and regulates recruitment to stress granules after oxidative stress. DeSUMOylation by SENP1 increases cytoplasmic TDP-43 localization. |
Co-immunoprecipitation of SUMO-TDP-43, site-directed mutagenesis (K136R), SENP1 overexpression, cell-permeable SENP1 peptide TS-1, splicing assays, immunofluorescence |
Molecular neurobiology |
Medium |
34390468
|
| 2021 |
O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of TDP-43 suppresses TDP-43 aggregation and hyperphosphorylation and promotes TDP-43's mRNA splicing function. O-GlcNAcylation of TDP-43 promotes proper splicing of STMN2 mRNA, required for normal axonal outgrowth and regeneration. |
Biochemical O-GlcNAcylation assays, OGT inhibition/overexpression, splicing assays, Drosophila motor neuron overexpression with locomotion and lifespan readouts |
EMBO reports |
Medium |
33855783
|
| 2019 |
TDP-43 in pluripotent cells represses formation of paraspeckles by enhancing the polyadenylated short isoform of Neat1 lncRNA. TDP-43 promotes pluripotency by regulating alternative polyadenylation of transcripts encoding pluripotency factors including Sox2, partially protecting its 3'UTR from miR-21-mediated degradation. Conversely, paraspeckles sequester TDP-43 from mRNAs to promote exit from pluripotency. |
RNA-seq, TDP-43 knockdown/overexpression in mouse embryonic stem cells, alternative polyadenylation analysis, miRNA reporter assays, mouse embryo patterning phenotypes |
Molecular cell |
Medium |
31047794
|
| 2020 |
C9orf72-derived poly(GR) protein promotes aggregation of endogenous TDP-43 by mediating sequestration of full-length TDP-43 in an RNA-independent manner, inducing cytoplasmic TDP-43 inclusion formation. Poly(GR) also causes mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins, resulting in aberrant cytoplasmic accumulation of TDP-43. |
GFP-(GR)200 transgenic mouse model; immunofluorescence; co-immunoprecipitation; antisense oligonucleotide treatment; RNase treatment to confirm RNA-independence |
Science translational medicine |
Medium |
32878979
|
| 2019 |
TDP-43 knockdown in astrocytes causes accumulation of repetitive element transcripts (including endogenous retroviral sequences) and double-stranded RNA (dsRNA), which activates innate immune signaling through protein kinase R (PKR). Inhibition or knockdown of PKR blocks the pro-inflammatory response induced by TDP-43 loss. |
siRNA knockdown of TDP-43 in primary rat astrocytes, RNA-seq, immunofluorescence, immunoblotting, PKR chemical inhibition and siRNA knockdown |
Neurobiology of disease |
Medium |
31229690
|
| 2017 |
TDP-43 regulates cryptic exon inclusion in a cell-type-specific manner. Conditional deletion of TDP-43 in excitatory neurons or skeletal myocytes revealed that the majority of TDP-43-repressed cryptic exons are cell type-specific, with only some shared across stem cells, neurons, and myocytes. |
Conditional knockout mouse models (excitatory neurons and skeletal myocytes), RNA-seq identification of cryptic exons |
Molecular neurodegeneration |
Medium |
28153034
|
| 2022 |
Stage-specific genetic inactivation of Tardbp in oligodendrocyte lineage cells showed that OPCs require TDP-43 for survival (deletion causes cell loss and rapid regeneration), while oligodendrocytes become less sensitive as they mature. TDP-43 loss in oligodendrocytes causes missplicing of key myelination proteins (cryptic exon incorporation) and morphological defects including inappropriate wrapping of neuronal somata and blood vessels. |
Conditional in vivo Cre-lox deletion at specific oligodendrocyte lineage stages; transcriptional analysis; behavioral phenotyping; electron microscopy |
eLife |
Medium |
35311646
|
| 2021 |
DCTN1 binds TDP-43 through its CAP-Gly-basic supradomain, dynactin domain, and C-terminal region, preferentially via TDP-43's C-terminal region. The Perry disease-linked DCTN1 p.G71A mutation impairs this interaction. Overexpression of DCTN1(G71A), the dynactin-domain fragment, or C-terminal fragment induces cytoplasmic mislocalization and aggregation of TDP-43. |
Co-immunoprecipitation, truncation mutant mapping, overexpression of disease mutant DCTN1, immunofluorescence for TDP-43 localization |
International journal of molecular sciences |
Medium |
33924373
|
| 2019 |
TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis and co-localizes with endocytic proteins. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, while enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is exacerbated by endocytic impairment and suppressed by enhancement of endocytic function. |
Yeast genetics, Drosophila ALS model, co-localization with endocytic markers in ALS patient tissue, endocytosis modulation assays, protein level measurements |
Nature communications |
Medium |
29233983
|
| 2020 |
Cdc48 (VCP in mammals) physically interacts and co-localizes with TDP-43 in ALS patient tissue, and regulates TDP-43 turnover and toxicity together with its cofactor Ubx3 (implicated in endocytic function) in yeast. TDP-43 expression impairs endocytic function. |
Yeast genetic screen, co-immunoprecipitation in yeast and ALS patient tissue, toxicity and protein turnover assays, endocytic function measurements |
Molecular and cellular biology |
Medium |
31767634
|
| 2019 |
TARDBP overexpression induces impairment of the ubiquitin proteasome system (UPS). PTK2/FAK is a suppressor of neurotoxicity induced by UPS impairment downstream of TDP-43. PTK2 activation promotes phosphorylation of SQSTM1/p62 at S403 via TBK1, impairing autophagic degradation of poly-ubiquitinated proteins. Non-phosphorylatable SQSTM1(S403A) reduces insoluble poly-ubiquitinated proteins and neurotoxicity caused by TDP-43 overexpression. |
Kinase inhibitor screen, Drosophila genetic model, site-directed mutagenesis (SQSTM1 S403A), co-immunoprecipitation, proteasome activity assays, TBK1 epistasis |
Autophagy |
Medium |
31690171
|
| 2021 |
CHMP2B regulates TDP-43 phosphorylation and toxicity independent of autophagy via CK1. Downregulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in Drosophila and mammalian cells. CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and proteasome-mediated turnover of CK1. |
Drosophila genetic screen, siRNA knockdown in mammalian cells, CK1 inhibition, ubiquitination assays, proteasome assays, immunoblotting |
The Journal of cell biology |
Medium |
34726688
|
| 2019 |
TDP-43 broadly affects transcription of protein-coding genes and Alu retrotransposons genome-wide. Loss of TDP-43 results in increased transcription activity near repetitive Alu elements within expressed genes, with the highest densities in shorter genes (<30 kb) whose transcription is most affected by TDP-43. |
GRO-seq (global run-on sequencing), TDP-43 knockdown in HEK293T cells, ChIP for TDP-43 at transcribed regions |
Biochimica et biophysica acta |
Medium |
31655156
|
| 2023 |
HSP70 and HSP90 chaperones promote TDP-43 phase separation, while HSP40 co-chaperones (DNAJA2, DNAJB1, DNAJB4, DNAJC7) show distinct effects on TDP-43 de-mixing. Chaperones and co-chaperones primarily recognize structured helical elements in TDP-43's prion-like domain. Methionine sulfoxidation of the second helical element impairs phase separation, amyloid formation, chaperone recognition, and alters phosphorylation by CK1δ. |
NMR structural characterization of TDP-43 prion-like domain, in vitro phase separation assays with purified chaperones, methionine sulfoxidation, kinase phosphorylation assays |
Nature communications |
Medium |
36709343
|
| 2021 |
Cytoplasmic TDP-43 associates with polyribosomes in an SH-SY5Y cellular stress model and is detected on polyribosomes in FTD brain lysate, supporting a role for cytoplasmic TDP-43 in translational control during stress. Sorbitol-driven cytoplasmic TDP-43 accumulation followed by oxidative stress triggers PARP cleavage and cellular toxicity. |
Polyribosome fractionation, immunofluorescence, PARP cleavage assays, brain lysate analysis |
Human molecular genetics |
Medium |
34378050
|
| 2022 |
TDP-43 oligomerization and phase separation properties are both essential for TDP-43 autoregulation (negative feedback via binding to its own 3'UTR). RNA binding to the central autoregulatory 3'UTR sequence induces TDP-43 condensation in cell lysates. ALS-associated mutation M337V disrupts liquid properties of TDP-43-RNA condensates and autoregulatory function, and decreases cellular clearance of TDP-43. |
Phase separation assays with purified TDP-43 variants, cell lysate condensation assays, autoregulatory reporter assays, FRAP, fluorescence anisotropy binding assays |
Frontiers in neuroscience |
Medium |
35495061
|
| 2025 |
During oxidative stress, TDP-43 is SUMO2/3-ylated by the SUMO E3 ligase PIAS4 within stress granules. Inhibition of TDP-43 SUMO2/3-ylation or PIAS4 depletion leads to irreversible TDP-43 aggregation in stress granules. Binding of TDP-43 to UG-rich RNA antagonizes PIAS4-mediated SUMO2/3-ylation, while RNA dissociation promotes it. SUMO2/3-ylation stabilizes cytosolic RNA-free TDP-43 against aggregation. |
SUMO conjugation assays, PIAS4 knockdown/inhibition, stress granule assembly assays, RNA binding mutants, immunofluorescence, biochemical aggregation assays |
Science advances |
Medium |
39982984
|
| 2024 |
TDP-43 loss of function induces cryptic alternative polyadenylation (APA) events including alternative last exons (ALE), 3'UTR extensions, and intronic polyadenylation. TDP-43 can have both repressive and enhancing action on APA. Cryptic 3'UTR extensions in transcription factors (e.g., ELK1, SIX3, TLX1) lead to increased RNA stability, higher cytoplasmic localisation, and increased wild-type protein translation. |
Custom bioinformatic APA pipeline, RNA-seq and Ribo-seq, TDP-43 depletion in cells, post-mortem ALS/FTD brain RNA-seq validation |
bioRxivpreprint |
Medium |
38313254
|
| 2023 |
EV-D68 protease 3C cleaves TDP-43 at residue Q327, generating fragments with substantially decreased solubility that promote TDP-43 aggregation and cytotoxicity. EV-D68 protease 2A induces TDP-43 cytoplasmic translocation. |
Viral infection assays, protease activity assays, site-specific cleavage mapping (Q327), solubility fractionation, cytotoxicity assays, lopinavir inhibitor experiments |
Journal of virology |
Medium |
37039659
|
| 2017 |
TDP-43 regulates the biogenesis of a number of miRNAs; TDP-43 knockdown alters miRNA expression profiles, miRNA isoform patterns (isomiRs), and miRNA arm selection. TDP-43 increases miR-500a-3p expression and binds the mature miR-500a-3p sequence. TDP-43 may promote lung cancer cell migration by regulating miR-423-3p. |
siRNA-mediated TDP-43 knockdown, small RNA-seq, RNA immunoprecipitation of mature miRNA sequence |
Protein & cell |
Low |
28952053
|
| 2019 |
TDP-43 and FUS interactomes were determined in HEK293T cells before and after DNA damage. TDP-43 binds to multiple factors important for DNA repair mechanisms including replication-dependent and -independent pathways, with selected interactions validated by co-immunoprecipitation. |
Mass spectrometry interactome profiling, co-immunoprecipitation validation, DNA damage induction in HEK293T cells |
Journal of proteome research |
Low |
31693373
|