protein

TDP-43

Entity Detail — Knowledge Graph Node

Understanding Entity Pages

This page aggregates everything SciDEX knows about TDP-43: its mechanistic relationships (Knowledge Graph edges), hypotheses targeting it, analyses mentioning it, and supporting scientific papers. The interactive graph below shows its immediate neighbors. All content is AI-synthesized from peer-reviewed literature.

2645Connections

29Hypotheses

15Analyses

50Outgoing

50Incoming

1Experiments

17Debates

Summary

TAR DNA-binding protein 43, an RNA/DNA-binding protein central to ALS, FTD, and AD pathology.

View on Wiki →

No AI portrait yet

🔬 Protein Info

Gene Symbol	TDP
Aliases	TDP-43
Chromosome	1p36.
Function	TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and is commonly co-detected in Alzheimer's disease as a secondary pathology.
Primary Expression	TDP-43 is ubiquitously expressed with high neuronal expression; pathological aggregation primarily affects motor neurons, cortical neurons, and hippocampal neurons
Subcellular Localization	signal (
GeneCards	TDP
Human Protein Atlas	TDP
Primary Target	TDP-43 protein aggregates (cytoplasmic inclusions) including C-terminal fragments (CTFs, 25 kDa and 35 kDa species) and phosphorylated TDP-43 (pSer409/410) aggregates
E3 Ligase	CRBN (cereblon) - the same target exploited by immunomodulatory imide drugs (IMiDs)
Target Type	Molecular glue / Induced proximityducer (~400 Da)
Progressive Supranuclear Palsy (PSP)	Some cases show TDP-43 co-pathology
Corticobasal Degeneration (CBD)	TDP-43 present in ~50% of cases
Alzheimer's Disease	TDP-43 pathology in ~30% of cases, correlates with cognitive decline
Associated Diseases	Ad, Aging, Als, ALS-FTD, ALS/FTLD
Known Drugs/Compounds	ASO, PROTAC, rapamycin, RAPAMYCIN, Rna Oligonucleotides, RNA oligonucleotides
Interactions	14-3-3θ, 4R-TAU, Actin, AGING, ALPHA-SYNUCLEIN, ALS
KG Connections	1722 knowledge graph edges
Databases	GeneCards UniProt NCBI Gene HPA STRING

🔮 Predicted Structure: TDP-43 — AlphaFold Q13148 Click to expand

AI-predicted structure from AlphaFold | Powered by Mol*

Wiki Pages (21)

Knowledge base pages for this entity

Canonical Page

Pathway Diagram

graph TD
    TDP_43["TDP-43"]
    TDP_43 -->|"activates"| mitochondrial_permeability_tra["mitochondrial permeability transition pore"]
    TDP_43 -->|"causes"| mitochondrial_DNA["mitochondrial DNA"]
    TDP_43 -->|"activates"| NF__B["NF-kappaB"]
    TDP_43 -->|"activates"| mPTP["mPTP"]
    TDP_43 -->|"causes"| ALS["ALS"]
    TDP_43 -.biomarker for.-> frontotemporal_lobar_degenerat["frontotemporal lobar degeneration"]
    TDP_43 -->|"expressed in"| neuron["neuron"]
    TDP_43 -->|"regulates"| translation_fidelity["translation fidelity"]
    ANXA11["ANXA11"] -->|"interacts"| TDP_43
    CSNK1D["CSNK1D"] -->|"phosphorylates"| TDP_43
    progranulin["progranulin"] -->|"regulates"| TDP_43
    ALS -->|"interacts"| TDP_43
    TARDBP["TARDBP"] -->|"encodes"| TDP_43
    APOE4["APOE4"] -->|"activates"| TDP_43
    GGGGCC_repeat_RNA["GGGGCC repeat RNA"] -->|"regulates"| TDP_43
    NEAT1["NEAT1"] -->|"regulates"| TDP_43
    C9orf72["C9orf72"] -->|"regulates"| TDP_43
    MITOCHONDRIAL_DNA["MITOCHONDRIAL DNA"] -->|"activates"| TDP_43

Outgoing (1295)

Target	Relation	Type	Str
LDLR	binds	gene	1.00
oligomerization	regulates	process	1.00
STABILITY	regulates	process	1.00
HMGCS1	binds	gene	1.00
AGGREGATION	causes	process	1.00
HMGCR	binds	gene	1.00
SREBF2	binds	gene	1.00
RNA binding	regulates	process	1.00
PKN1	regulates	gene	0.95
Neurodegeneration	associated_with	process	0.95
frontotemporal lobar degeneration	biomarker_for	disease	0.95
Frontotemporal Dementia	causes	disease	0.95
Alzheimer'S Disease	associated_with	disease	0.95
Als	associated_with	disease	0.95
FTLD	associated_with	disease	0.95
Cryptic Splicing	regulates	process	0.95
Mitochondrial DNA Release	associated_with	process	0.95
TDP-43 K181E	associated_with	biomarker	0.95
FTLD-TDP	associated_with	disease	0.95
KCNQ2	regulates	gene	0.95
Cryptic Exon Splicing	inhibits	process	0.95
UNC13A	regulates	gene	0.95
Rna Splicing	modulates	process	0.95
Frontotemporal Lobar Degeneration	biomarker_for	disease	0.95
RNA Splicing	involved_in	process	0.95
Gene Expression	regulates	process	0.95
Rna Splicing	involved_in	process	0.95
ALS/FTLD	associated_with	disease	0.95
Alternative Splicing	regulates	process	0.95
Alzheimer'S Disease	biomarker_for	disease	0.95
Cryptic Exon Inclusion	inhibits	process	0.95
Aggregation	involved_in	process	0.95
Ad	associated_with	disease	0.95
mRNA Splicing	regulates	process	0.95
UG-rich RNA sequences	binds	compound	0.95
Nuclear Depletion	causes	phenotype	0.95
LC3ylation	regulates	process	0.95
UNC13A	inhibits	gene	0.95
NEAT1	regulates	gene	0.95
Cytoplasmic Aggregation	causes	phenotype	0.95
RNA Dysregulation	causes	process	0.95
Splicing Repression	regulates	process	0.95
Ftld	associated_with	disease	0.95
Nuclear Condensation	involved_in	process	0.95
ALS-FTD	associated_with	disease	0.95
Frontotemporal Lobar Degeneration	associated_with	disease	0.95
Tdp-43 Proteinopathies	involved_in	disease	0.95
Amyotrophic Lateral Sclerosis	associated_with	disease	0.93
Mis-splicing	mediates	process	0.93
Cytoplasmatic Mislocalization	involved_in	phenotype	0.93

Incoming (1350)

Source	Relation	Type	Str
entities-mitochondrial-dynamics	interacts_with	wiki	0.00
entities-histone-modifications	interacts_with	wiki	0.00
p38α MAPK	phosphorylates	protein	1.00
SUMO2/3	conjugates	protein	1.00
TARDBP	associated_with	gene	1.00
14-3-3θ	interacts_with	protein	0.95
MOTOR NEURONS	inhibits	cell_type	0.95
STEM CELLS	activates	cell_type	0.95
Stress Granules	involved_in	cell_type	0.95
TAU	interacts_with	protein	0.95
cAMP/PKA Signaling	regulates	pathway	0.95
FRONTOTEMPORAL DEMENTIA	interacts_with	disease	0.95
ATXN2	suppresses	gene	0.95
TREM2	interacts_with	protein	0.95
FUS	interacts_with	gene	0.95
ASRGL1	regulates	gene	0.95
NEURON	interacts_with	cell_type	0.95
Stress	activates	phenotype	0.92
ANXA11	associated_with	protein	0.90
TDP-43 Aggregates	associated_with	protein	0.90
G4C2 Hexanucleotide Repeat Expansion	associated_with	mechanism	0.90
MAPK	phosphorylates	pathway	0.90
Loss Of Asrgl1	causes	mechanism	0.90
ASRGL1	substrate_of	protein	0.90
Phosphatidylserine	promotes	compound	0.85
ASRGL1	degrades	gene	0.85
Cardiolipin	promotes	compound	0.85
Rna Oligonucleotides	inhibits	compound	0.85
NUFIP2	interacts_with	gene	0.85
Oxidative Stress	activates	process	0.85
Mistranslation	exacerbates	process	0.85
SRRM2	interacts_with	gene	0.85
TDP-43 Fibrils	phosphorylates	compound	0.85
RNA oligonucleotides	targets	compound	0.85
Ubiquitin-Proteasome System	degrades	pathway	0.85
RNA	activates	gene	0.85
Hyperphosphorylation	modulates	process	0.85
Cleavage	modulates	process	0.85
Ubiquitination	modulates	process	0.85
CHMP7	modulates	protein	0.85
RNA	regulates	gene	0.85
RNA	interacts_with	gene	0.85
ATAXIN-2	interacts_with	protein	0.85
HNRNPC	regulates	gene	0.80
STMN2	regulates	gene	0.80
Cysteine Oxidation	associated_with	process	0.80
OPTN	co_localizes	protein	0.80
ASRGL1	interacts_with	protein	0.80
AMYLOID	interacts_with	protein	0.80
P38	associated_with	gene	0.80

Targeting Hypotheses (29)

Hypotheses where this entity is a therapeutic target

Hypothesis	Score	Disease	Analysis
p38α Inhibitor and PRMT1 Activator Combination to Restore Ph	0.848	neurodegeneration	What is the therapeutic window between i
Microglial AIM2 Inflammasome as the Primary Driver of TDP-43	0.824	neurodegeneration	What are the mechanisms by which gut mic
HSPB1 Phosphorylation Mimetics to Promote Protective TDP-43	0.820	neurodegeneration	What is the therapeutic window between i
H3: G3BP1 as Nucleation Hub for TDP-43/FUS Seeding	0.743	neurodegeneration	How do pathological stress granules tran
TDP-43 condensation thermodynamics as a therapeutic target a	0.710	neuroscience	How can subcellular compartmentalization

STMN2 Restoration as a Prerequisite for Axon Growth After TD	0.683	neurodegeneration	What molecular mechanisms enable functio
SASP-Secreted MMP-9 from Senescent Microglia Generates Patho	0.682	ALS	What are the mechanisms by which microgl
Glial Neuroinflammatory Amplification by TDP-43 Pathology	0.680	neurodegeneration	What mechanisms underlie TDP-43's contri
TDP-43 Pathology Disrupts the HGS-PYGB Autophagy Receptor Ca	0.678	neurodegeneration	What mechanisms underlie neuronal resist
Cyclophilin D (CypD) Displacement by Mitochondrial TDP-43	0.656	neurodegeneration	What upstream mechanisms cause TDP-43 to
Nuclear TDP-43 Depletion Drives Synaptic Splicing Dysregulat	0.620	neurodegeneration	Gap 006 analysis (archived stub)
Cytosolic TDP-43 aggregation sequesters SNAP29 and syntaxin-	0.600	neurodegeneration	What are the neuron-specific effects of
Aβ42 oligomers drive TDP-43 phosphorylation at s409/410 thro	0.595	neurodegeneration	What mechanisms drive TDP-43 pathology s
Aβ-induced downregulation of circPDS5B derepresses TDP-43 mR	0.595	neurodegeneration	What mechanisms drive TDP-43 pathology s
Nuclear Export Deficits Increase Cytosolic TDP-43 Burden	0.580	neurodegeneration	What determines the specificity of TDP-4
Neuroinflammation-Driven TDP-43 Mislocalization via Microgli	0.580	neurodegeneration	How does APOE4 mechanistically increase
TDP-43 Cryptic Exon–Targeted ASOs to Restore Hippocampal Gam	0.577	neurodegeneration	RNA binding protein dysregulation across
Autophagy-Lysosomal Flux Impairment Preventing Pathological	0.500	neurodegeneration	How does APOE4 mechanistically increase
VDAC1 Hyper-Oligomerization via Direct TDP-43 Binding	0.496	neurodegeneration	What upstream mechanisms cause TDP-43 to
G3BP1-TDP-43 Cross-Seeding Drives Co-Aggregation That Prion-	0.490	neurodegeneration	How do disease-associated mutations in G
Hyperphosphorylated TDP-43 Traps TRIM21 Into Inactive Comple	0.487	neurodegeneration	How do pathological stress granules in n
TDP-43 Pathology Creates a Distinct Epigenetic Clock "Signat	0.483	-	Epigenetic clocks as biomarkers for Alzh
Mitochondrial Dysfunction Increasing Neuronal Vulnerability	0.470	neurodegeneration	How does APOE4 mechanistically increase
RNA-Binding Competition Therapy for TDP-43 Cross-Seeding	0.465	neurodegeneration	Protein aggregation cross-seeding across
Necroptosis-cGAS Feedforward Loop Converts TDP-43 Pathology	0.460	neuroinflammation	How does chronic cGAS/STING activation d
TSPO-Mediated TDP-43 Mitochondrial Import	0.460	neurodegeneration	What determines the specificity of TDP-4
Age-dependent downregulation of KPNA2 creates limbic neuron-	0.452	neurodegeneration	What mechanisms drive TDP-43 pathology s
DNA Damage Repair Dysfunction Creating TDP-43 Pathology Feed	0.430	neurodegeneration	How does APOE4 mechanistically increase
Direct APOE4-TDP-43 Protein-Protein Interaction Promoting Ag	0.360	neurodegeneration	How does APOE4 mechanistically increase

Mentioning Analyses (15)

Scientific analyses that reference this entity

Is ferroptosis the primary driver of motor neuron death in ALS or an epiphenomen

neurodegeneration | 2026-04-18 | 4 hypotheses Top: 0.538

Comparative epigenetic signatures across AD, PD, and ALS

neurodegeneration | 2026-04-16 | 7 hypotheses Top: 0.550

What molecular mechanisms enable functional recovery and muscle re-innervation a

neurodegeneration | 2026-04-14 | 2 hypotheses Top: 0.683

What are the specific design principles for small molecules that can selectively

medicinal chemistry | 2026-04-10 | 0 hypotheses

What determines the selectivity and efficiency of intercellular transmission pat

neurodegeneration | 2026-04-08 | 0 hypotheses

Experiments (1)

Experimental studies targeting or related to this entity

Experiment	Type	Disease	Score	Feasibility	Model	Status	Est. Cost
MAPK pathway inhibition by QTJD through butyrate mechanism	exploratory	Mycoplasma pneumoniae pneumoni	0.900	0.00	Mouse macrophages	proposed	N/A

Related Papers (0)

Scientific publications cited in analyses involving this entity

Title & PMID	Authors	Journal	Year	Citations
No papers found

Debates (17)

Multi-agent debates referencing this entity

The study establishes G3BP1's role as a tunable switch for stress granule assemb

closed · Rounds: 4 · Score: 0.69 · 2026-04-22

While the study establishes TDP-43 triggers mtDNA release via mPTP to activate c

closed · Rounds: 4 · Score: 0.73 · 2026-04-21

The abstract identifies APOE4 association with increased TDP-43 pathology but th

closed · Rounds: 4 · Score: 0.61 · 2026-04-21

The study identifies cGAS/STING activation as a consequence of TDP-43-mediated m

closed · Rounds: 4 · Score: 0.73 · 2026-04-21

TDP-43 inclusions occur in AD, ALS, and FTLD but the pathogenic mechanisms leadi

closed · Rounds: 4 · Score: 0.70 · 2026-04-21

While the study demonstrates TDP-43 triggers mPTP-mediated mtDNA release, the mo

closed · Rounds: 4 · Score: 0.77 · 2026-04-21

AD patients with TDP-43 pathology show worse cognitive impairment, but how TDP-4

closed · Rounds: 4 · Score: 0.73 · 2026-04-21

The debate identified that TDP-43 undergoes both normal and pathological phase s

closed · Rounds: 4 · Score: 0.43 · 2026-04-21

What are the shared DNA methylation age acceleration and histone modification pa

closed · Rounds: 4 · Score: 0.50 · 2026-04-18

The debate highlighted compelling correlative evidence for ferroptosis markers i

closed · Rounds: 4 · Score: 0.50 · 2026-04-18

Related Research

Hypotheses and analyses mentioning TDP-43 in their description or question text

STMN2 Restoration as a Prerequisite for Axon Growth After TDP-43 Clearance

Score: 0.683 · neurodegeneration · 2026-04-14

**Molecular Mechanism and Rationale** The molecular foundation of STMN2 restoration as a prerequisite for axonal regene

SASP-Secreted MMP-9 from Senescent Microglia Generates Pathological TDP-43 C-Ter

Score: 0.682 · ALS · 2026-04-26

Glial Neuroinflammatory Amplification by TDP-43 Pathology

Score: 0.680 · neurodegeneration · 2026-04-21

## Mechanistic Overview Glial Neuroinflammatory Amplification by TDP-43 Pathology starts from the claim that modulating

TDP-43 Pathology Disrupts the HGS-PYGB Autophagy Receptor Cascade in Motor Neuro

Score: 0.678 · neurodegeneration · 2026-04-26

TDP-43 aggregates sequester hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), a critical hub coordinat

Cyclophilin D (CypD) Displacement by Mitochondrial TDP-43

Score: 0.656 · neurodegeneration · 2026-04-21

## Mechanistic Overview Cyclophilin D (CypD) Displacement by Mitochondrial TDP-43 starts from the claim that modulating

Nuclear TDP-43 Depletion Drives Synaptic Splicing Dysregulation in ALS-FTD

Score: 0.620 · neurodegeneration · 2026-04-22

## Mechanistic Overview Nuclear TDP-43 Depletion Drives Synaptic Splicing Dysregulation in ALS-FTD starts from the claim

Cytosolic TDP-43 aggregation sequesters SNAP29 and syntaxin-17, blocking autopha

Score: 0.600 · neurodegeneration · 2026-04-21

## Mechanistic Overview Cytosolic TDP-43 aggregation sequesters SNAP29 and syntaxin-17, blocking autophagosome-lysosome

Aβ42 oligomers drive TDP-43 phosphorylation at s409/410 through CDK5/p25 activat

Score: 0.595 · neurodegeneration · 2026-04-21

**Molecular Mechanism and Rationale** The hypothesis centers on a novel mechanistic pathway linking amyloid-β42 (Aβ42)

Aβ-induced downregulation of circPDS5B derepresses TDP-43 mRNA translation in li

Score: 0.595 · neurodegeneration · 2026-04-21

**Molecular Mechanism and Rationale** The proposed mechanism centers on a complex regulatory network involving circPDS5

Nuclear Export Deficits Increase Cytosolic TDP-43 Burden

Score: 0.580 · neurodegeneration · 2026-04-21

**Molecular Mechanism and Rationale** The nuclear export machinery represents a critical checkpoint in cellular homeost

Neuroinflammation-Driven TDP-43 Mislocalization via Microglial APOE4 Signaling

Score: 0.580 · neurodegeneration · 2026-04-21

**Molecular Mechanism and Rationale** The proposed mechanism centers on a complex inflammatory cascade initiated by APO

TDP-43 Cryptic Exon–Targeted ASOs to Restore Hippocampal Gamma Oscillations

Score: 0.577 · neurodegeneration · 2026-04-13

## Mechanistic Overview TDP-43 Cryptic Exon–Targeted ASOs to Restore Hippocampal Gamma Oscillations starts from the clai

Autophagy-Lysosomal Flux Impairment Preventing Pathological TDP-43 Clearance

Score: 0.500 · neurodegeneration · 2026-04-21

## Mechanistic Overview Autophagy-Lysosomal Flux Impairment Preventing Pathological TDP-43 Clearance starts from the cla

VDAC1 Hyper-Oligomerization via Direct TDP-43 Binding

Score: 0.496 · neurodegeneration · 2026-04-21

## Mechanistic Overview VDAC1 Hyper-Oligomerization via Direct TDP-43 Binding starts from the claim that modulating VDAC

G3BP1-TDP-43 Cross-Seeding Drives Co-Aggregation That Prion-Spreads Across Neura

Score: 0.490 · neurodegeneration · 2026-04-22

## Mechanistic Overview G3BP1-TDP-43 Cross-Seeding Drives Co-Aggregation That Prion-Spreads Across Neural Circuits start

TDP-43

Understanding Entity Pages

Summary

Wiki Pages (21)

Molecular Glue for TDP-43 Aggregate Clearance

TDP-43 Proteinopathy

TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis

TAR DNA-Binding Protein 43 (TDP-43)

TDP-43 Protein

Update TDP-43 protein page with comprehensive content

Mechanism: Progranulin Loss and TDP-43 Pathology in FTD

Therapeutic Hypothesis: TDP-43 and a-synuclein pathologies in the amygdala...

VCP→TDP-43→ALS/FTD Causal Chain

AD-FTD Tau-TDP-43 Overlap: Mechanism Comparison

TDP-43 (TAR DNA-Binding Protein 43) - Biomarker

TARDBP Protein (TDP-43)

TDP-43 Pathology in Corticobasal Syndrome

TDP-43 Co-pathology in Corticobasal Syndrome

Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)

TDP-43 Proteinopathy in ALS

LATE (Limbic-Predominant Age-Related TDP-43 Encephalopathy)

TDP-43 RNA Granule Pathway

Cryptic Exon Splicing in TDP-43 Proteinopathy

TDP-43 DNA Repair Mechanism in ALS and Dementia

TDP-43 Pathology Reversibility in ALS

Pathway Diagram

Outgoing (1295)

Incoming (1350)

Targeting Hypotheses (29)

Mentioning Analyses (15)

Is ferroptosis the primary driver of motor neuron death in ALS or an epiphenomen

Comparative epigenetic signatures across AD, PD, and ALS

What molecular mechanisms enable functional recovery and muscle re-innervation a

What are the specific design principles for small molecules that can selectively

What determines the selectivity and efficiency of intercellular transmission pat

What mechanisms underlie TDP-43's contribution to cognitive impairment severity

What upstream mechanisms cause TDP-43 to trigger mPTP opening and can this be th

What mechanisms drive TDP-43 pathology specifically in Alzheimer's disease versu

How does chronic cGAS/STING activation downstream of TDP-43 contribute to progre

How does APOE4 mechanistically increase TDP-43 pathology frequency in Alzheimer'

What determines the specificity of TDP-43-induced mitochondrial DNA release for

How do disease-associated mutations in G3BP1 or its binding partners alter stres

RNA binding protein dysregulation across ALS FTD and AD

TDP-43 phase separation therapeutics for ALS-FTD

Protein aggregation cross-seeding across neurodegenerative diseases

Experiments (1)

Related Papers (0)

Debates (17)

The study establishes G3BP1's role as a tunable switch for stress granule assemb

While the study establishes TDP-43 triggers mtDNA release via mPTP to activate c

The abstract identifies APOE4 association with increased TDP-43 pathology but th

The study identifies cGAS/STING activation as a consequence of TDP-43-mediated m

TDP-43 inclusions occur in AD, ALS, and FTLD but the pathogenic mechanisms leadi

While the study demonstrates TDP-43 triggers mPTP-mediated mtDNA release, the mo

AD patients with TDP-43 pathology show worse cognitive impairment, but how TDP-4

The debate identified that TDP-43 undergoes both normal and pathological phase s

What are the shared DNA methylation age acceleration and histone modification pa

The debate highlighted compelling correlative evidence for ferroptosis markers i

Related Research

STMN2 Restoration as a Prerequisite for Axon Growth After TDP-43 Clearance

SASP-Secreted MMP-9 from Senescent Microglia Generates Pathological TDP-43 C-Ter

Glial Neuroinflammatory Amplification by TDP-43 Pathology

TDP-43 Pathology Disrupts the HGS-PYGB Autophagy Receptor Cascade in Motor Neuro

Cyclophilin D (CypD) Displacement by Mitochondrial TDP-43

Nuclear TDP-43 Depletion Drives Synaptic Splicing Dysregulation in ALS-FTD

Cytosolic TDP-43 aggregation sequesters SNAP29 and syntaxin-17, blocking autopha

Aβ42 oligomers drive TDP-43 phosphorylation at s409/410 through CDK5/p25 activat

Aβ-induced downregulation of circPDS5B derepresses TDP-43 mRNA translation in li

Nuclear Export Deficits Increase Cytosolic TDP-43 Burden

Neuroinflammation-Driven TDP-43 Mislocalization via Microglial APOE4 Signaling

TDP-43 Cryptic Exon–Targeted ASOs to Restore Hippocampal Gamma Oscillations

Autophagy-Lysosomal Flux Impairment Preventing Pathological TDP-43 Clearance

VDAC1 Hyper-Oligomerization via Direct TDP-43 Binding

G3BP1-TDP-43 Cross-Seeding Drives Co-Aggregation That Prion-Spreads Across Neura