TAR DNA-Binding Protein 43 (TDP-43)

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TAR DNA-Binding Protein 43 (TDP-43)

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TAR DNA-Binding Protein 43 (TDP-43)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">TAR DNA-Binding Protein 43 (TDP-43)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[TARDBP](/genes/tardbp)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q13148" target="_blank">Q13148</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2N4P" target="_blank">2N4P</a>, <a href="https://www.rcsb.org/structure/5E1O" target="_blank">5E1O</a>, <a href="https://www.rcsb.org/structure/6N3T" target="_blank">6N3T</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>44.7 kDa (full-length), 43 kDa (cleaved)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Nucleus, cytoplasm</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Heterogeneous nuclear ribonucleoprotein (hnRNP) family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Amyotrophic Lateral Sclerosis](/diseases/als), [Frontotemporal Dementia](/diseases/ftd), [Alzheimer's Disease](/diseases/alzheimers)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">16 edges</a></td>
</tr>
</table>

TAR DNA-Binding Protein 43 (TDP-43)

Overview

...

TAR DNA-Binding Protein 43 (TDP-43)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">TAR DNA-Binding Protein 43 (TDP-43)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[TARDBP](/genes/tardbp)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q13148" target="_blank">Q13148</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2N4P" target="_blank">2N4P</a>, <a href="https://www.rcsb.org/structure/5E1O" target="_blank">5E1O</a>, <a href="https://www.rcsb.org/structure/6N3T" target="_blank">6N3T</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>44.7 kDa (full-length), 43 kDa (cleaved)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Nucleus, cytoplasm</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Heterogeneous nuclear ribonucleoprotein (hnRNP) family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Amyotrophic Lateral Sclerosis](/diseases/als), [Frontotemporal Dementia](/diseases/ftd), [Alzheimer's Disease](/diseases/alzheimers)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">16 edges</a></td>
</tr>
</table>

TAR DNA-Binding Protein 43 (TDP-43)

Overview

TAR DNA-Binding Protein 43 (TDP-43) is a 414-amino acid nuclear protein encoded by the TARDBP gene on chromosome 1p36.22 that plays a critical role in RNA metabolism and has emerged as a central player in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)[@neumann2006]. [TDP-43](/mechanisms/tdp-43-proteinopathy) is the major constituent of cytoplasmic inclusions found in approximately 95% of ALS cases and 50% of FTD cases, making it one of the most important pathological proteins in neurodegenerative disease[@arai2006].

The discovery of TDP-43 as the pathological protein in ALS and FTD in 2006 by Neumann et al. revolutionized our understanding of these diseases and revealed unexpected links between apparently distinct neurodegenerative conditions[@neumann2006]. This 43 kDa protein, initially characterized as a transcriptional repressor binding to the TAR DNA element of HIV-1, has since been shown to be a master regulator of RNA metabolism with roles in splicing, stability, transport, and translation.

Molecular Structure

TDP-43 contains several distinct structural domains, each with specific functional properties:

N-Terminal Domain (residues 1-102)

The N-terminal domain contains:

Nuclear Localization Signal (NLS): Residues 82-98, a basic region mediating importin-α/β binding
Dimerization domain: Enables TDP-43 to form homodimers and higher-order oligomers
Nuclear export signal (NES): Recently identified in this region

The NLS is crucial for nuclear import, and mutations or post-translational modifications affecting this region contribute to disease pathogenesis.

RNA Recognition Motif 1 (RRM1, residues 106-176)

RRM1 is the primary RNA/DNA-binding domain:

Recognition motif: RRM1 has high affinity for UG-rich sequences (TAR DNA, UG repeats)
Structure: Classical RRM fold with RNP1 and RNP2 consensus sequences
Binding specificity: Single-stranded DNA and RNA, with preference for pyrimidine-rich sequences
Function: Mediates both transcriptional repression and RNA splicing regulation

RNA Recognition Motif 2 (RRM2, residues 191-259)

RRM2 works in concert with RRM1:

Auxiliary RNA binding: Enhances specificity and affinity for target RNAs
Splicing regulation: Critical for exon skipping events (e.g., CFTR exon 9, SMN2 exon 7)
Structural role: Stabilizes RRM1 binding through inter-domain interactions

Glycine-Rich Domain (residues 274-306)

The glycine-rich region mediates protein-protein interactions:

HnRNP interactions: Binds to other hnRNP proteins (A1, A2/B1, C)
Splicing factors: Interacts with spliceosomal components
transcriptional co-activators: Associates with p300/CBP and other regulators

C-Terminal Prion Domain (residues 307-414)

The C-terminal region is intrinsically disordered and aggregation-prone:

Q/N-rich sequence: Glutamine/asparagine-rich prion-like domain
Aggregation nucleation: Site of pathological aggregation in disease
Most disease mutations: >90% of ALS-associated TARDBP mutations occur here
Stress granule recruitment: Mediates liquid-liquid phase separation

Post-Translational Modifications

TDP-43 undergoes numerous PTMs that regulate its function and aggregation:

| Modification | Site | Effect |
|--------------|------|--------|
| Phosphorylation | Ser379, Ser409, Ser410, Ser383/Ser409 | Marker of pathological aggregation |
| Ubiquitination | Multiple Lys residues | Degradation signal, found in inclusions |
| SUMOylation | Lys | May protect from degradation |
| Acetylation | Multiple Lys | Reduces RNA binding |
| Cleavage | Asp219, Asp89 | Generates aggregation-prone fragments |
| Methylation | Arg | Alters protein interactions |

Pathological Truncation

C-terminal truncation of TDP-43 is a hallmark of disease:

C-terminal fragments (CTFs): 25-35 kDa fragments found in inclusions
Generation by caspases: Caspase-3 cleavage at Asp219
Aggregation-prone: Truncated forms seed full-length protein aggregation
Toxicity: CTFs are more toxic than full-length protein

Normal Physiological Functions

RNA Processing

TDP-43 is a multifunctional RNA-binding protein involved in:

Alternative Splicing

TDP-43 regulates the splicing of hundreds of neuronal transcripts:

SMN2 exon 7: Critical modifier of spinal muscular atrophy
CFTR exon 9: Regulator of chloride channel splicing
NLGN1/3: Synaptic adhesion proteins
[MAPT](/proteins/tau) exon 10: Tau isoform regulation
UNC13A: Synaptic vesicle release

RNA Stability and Transport

3' UTR binding: Regulates mRNA stability
RNA transport granules: Facilitates dendritic mRNA localization
Translation regulation: Controls translation of target mRNAs
Long non-coding RNAs: Processing of MALAT1, NEAT1

Transcriptional Regulation

TAR DNA binding: Originally characterized as HIV-1 TAR repressor
Chromatin remodeling: Associates with epigenetic regulators
Gene expression: Modulates transcription of neuronal genes

Nuclear-Cytoplasmic Shuttling

TDP-43 dynamically shuttles between nucleus and cytoplasm[@cruz2011]:

Import: Importin-α/β mediated, requires NLS
Export: Exportin-1 (CRM1) dependent, requires NES
Stress conditions: Increased cytoplasmic localization
Cellular stress response: Stress granule formation

Stress Granule Biology

Under cellular stress, TDP-43 localizes to stress granules:

Formation: Liquid-liquid phase separation under stress
Composition: G3BP1, TIA-1, PABP1, other RBPs
Function: Temporarily sequester mRNAs for survival
Disease link: Prolonged stress → irreversible aggregation

DNA Binding Functions

Despite its name, TDP-43 has multiple DNA-binding functions:

Genomic integrity: Binds to DNA damage response elements
Telomere regulation: Associates with telomeric DNA
Retrotransposon control: May regulate LINE-1 elements

Pathogenesis in ALS and FTD

TDP-43 Proteinopathy

The hallmark of ALS/FTD is cytoplasmic TDP-43 inclusion formation:

Mermaid diagram (expand to render)

Loss of Nuclear Function

Cytoplasmic aggregation leads to nuclear depletion:

RNA splicing disruption: Loss of nuclear TDP-43 causes missplicing
Target transcript changes: >100 transcripts dysregulated
Neuronal vulnerability: Specific exon patterns affected
Cell death: Correlates with neurodegeneration

Toxic Gain-of-Function

Cytoplasmic aggregates cause toxicity through:

RNA sequestration: Traps other RBPs in aggregates
Stress granule persistence: Prevents stress recovery
Proteostasis disruption: Overwhelms degradation systems
Mitochondrial dysfunction: Indirect effects on energy metabolism

Key Disease Mutations

Over 50 mutations in TARDBP cause ALS/FTD[@rutherford2008]:

| Mutation | Location | Effect |
|----------|----------|--------|
| A315T | C-terminal | Most common, early onset |
| M337V | C-terminal | Highly penetrant |
| G348C | C-terminal | Rapid progression |
| N390D | C-terminal | Variable phenotype |
| Q331K | C-terminal | Motor neuron predominant |
| G294V | C-terminal | FTD predominant |
| K263E | RRM1 | Early onset |

Mechanisms of Neurodegeneration

RNA splicing disruption: Aberrant splicing of critical neuronal transcripts

Mitochondrial dysfunction: Energy metabolism impairment

Oxidative stress: Increased [ROS](/entities/reactive-oxygen-species) production

[Autophagy](/entities/autophagy) impairment: Defective protein clearance

Nucleocytoplasmic transport disruption: Nuclear pore dysfunction

Stress granule dysregulation: Persistent granules

TDP-43 Strains

Emerging evidence suggests TDP-43 forms distinct strains:

Conformational variants: Different aggregate structures
Cell-to-cell transmission: Prion-like propagation
Phenotypic variability: Strain differences may explain disease variability
Strain detection: RT-QuIC and other amplification assays

TDP-43 in Alzheimer's Disease

While not the primary pathology in AD, TDP-43 is commonly observed:

Prevalence: Found in up to 50% of AD cases
Distribution: Limbic regions, amygdala
Impact: May accelerate cognitive decline
Co-pathology: Often with tau and amyloid

LATE-NC

Limbic-predominant Age-related TDP-43 Encephalopathy:

Clinical syndrome: Late-onset dementia mimicking AD
Pathology: TDP-43 in limbic regions without ALS/FTD
Prevalence: Common in oldest-old
Biomarkers: Under development

Animal Models

Mouse Models

| Model | Mutation | Phenotype | Notes |
|-------|----------|-----------|-------|
| TDP-43Q331K | Human Q331K | Age-dependent motor dysfunction | Knockin |
| TDP-43M337V | Human M337V | Motor neuron degeneration | Transgenic |
| TDP-43ΔNLS | NLS deletion | Cytoplasmic aggregation | Inducible |
| TDP-43WT | Wild-type | Moderate pathology | Overexpression |

Key Findings from Models

Nuclear loss is sufficient: NLS mutation causes neurodegeneration
Cell non-autonomous: Glia contribute to pathology
Propagation: Injected seeds cause pathology
Therapeutic targets: Support multiple intervention strategies

Therapeutic Strategies

Small Molecule Approaches

Aggregation Inhibitors

Mosaicin: Natural compound reducing aggregation
Anle138b: Oligomer modulator, shows efficacy in mice
YKL-40: Chitinase-like protein, biomarker and target
Doxycycline: FDA-approved, shows promise in trials

Targeting Downstream Pathways

Autophagy enhancers: Rapamycin, trehalose
Antioxidants: CoQ10, edaravone
Anti-inflammatory: Microglial modulators

Antisense Oligonucleotides

ASO therapy represents a promising approach:

Mechanism: Reduce TDP-43 expression
Delivery: Intrathecal administration
Challenges: Need to maintain nuclear function
Status: Pre-clinical development

Gene Therapy Approaches

Wild-type TDP-43 delivery: Restore nuclear function
Anti-aggregation proteins: Molecular chaperones
RNA targeting: CRISPR-based approaches
Cell replacement: Stem cell therapies

Immunotherapy

Anti-TDP-43 antibodies: Active/passive immunization
Antibody engineering: Enhanced brain penetration
Vaccination strategies: Prevention in at-risk populations

Biomarkers

Cerebrospinal Fluid Biomarkers

| Biomarker | Change | Utility |
|-----------|--------|---------|
| Total TDP-43 | Increased | Disease progression |
| Phospho-TDP-43 | Increased | Specific to pathology |
| TDP-43 fragments | Increased | Disease severity |

Blood Biomarkers

[Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain (NfL): Disease progression marker
Phospho-TDP-43: Emerging blood test
Cell-free DNA: Potential for detection

Imaging

TDP-43 PET ligands: Under development
Structural MRI: Pattern of atrophy
PET markers: Metabolic changes

Genetics

TARDBP Mutations

Autosomal dominant: Most mutations
Variable penetrance: Age-dependent
Phenotypic spectrum: ALS to FTD
Population genetics: Founder effects in some groups

Risk Factors

Common variants: GWAS hits near TARDBP
Epigenetic changes: Altered methylation in disease
Gene expression: Dysregulation in affected tissues

ALS/FTD Genetic Overlap

[C9orf72](/entities/c9orf72): Most common genetic cause
FUS: Another RNA-binding protein
GRN: Progranulin, lysosomal function
TBK1: Autophagy/innate immunity

Neuropathology

Inclusion Types

Neuronal cytoplasmic inclusions (NCIs): Most common

Neuronal nuclear inclusions (NNIs): Less common

Glial inclusions: In some cases

Pristine inclusions: Rare, poorly characterized

Regional Distribution

ALS:

Motor [cortex](/brain-regions/cortex)
Spinal cord motor [neurons](/entities/neurons)
Bulbar nuclei
Frontal cortex (some cases)

FTD:

Frontal and temporal cortex
Basal ganglia
Limbic system
Motor cortex (overlap)

Staging Systems

ALS staging: Braak-like progression
FTD staging:新 cortical involvement
LATE staging: Limbic predominance

TDP-43 Interactome

Key Binding Partners

| Protein | Function | Disease Relevance |
|---------|----------|-------------------|
| hnRNP A1 | Splicing | Co-aggregation |
| hnRNP A2/B1 | RNA transport | Co-aggregation |
| FUS | RNA metabolism | ALS/FTD gene |
| TAF15 | Transcription | ALS/FTD gene |
| SMN complex | Splicing | SMA modifier |
| Importins | Nuclear import | Transport deficit |

RNA Targets

Critical transcripts: >30% of brain transcripts
Functional categories: Synaptic, mitochondrial, survival
Dysregulation patterns: Disease-specific signatures

Future Directions

Emerging Research Areas

Strain biology: Understanding TDP-43 variants

Propagation mechanisms: Cell-to-cell spread

Systems biology: Network-level understanding

Biomarker development: Early detection

Combination therapies: Multi-target approaches

Precision Medicine Approaches

Genetic stratification: Mutation-specific therapies
Biomarker-guided: Patient selection
Stage-specific: Early vs late intervention
Personalized: Individualized treatment plans

Cellular and Animal Models

In Vitro Models

Cell Lines

Motor neuron lines: NSC-34, MN-1 for disease modeling
HEK293T: Standard expression system
iPSC-derived neurons: Patient-specific models with TARDBP mutations
Astrocytes: Glial contribution to pathology

3D Culture Systems

Brain organoids: Patient-derived, show TDP-43 pathology
ALS-on-a-chip: Microfluidic models
Co-cultures: Neuron-glia interactions

In Vivo Models

Transgenic Mouse Models

| Model | Approach | Phenotype | Notes |
|-------|----------|-----------|-------|
| TDP-43WT | Wild-type overexpression | Motor dysfunction | Dose-dependent |
| TDP-43Q331K | Human mutant knockin | Age-dependent ALS | Most physiological |
| TDP-43M337V | Mutant overexpression | Rapid onset | Robust phenotype |
| TDP-43ΔNLS | NLS deletion | Cytoplasmic TDP-43 | Loss of nuclear function |
| Tg(WT) | Wild-type expression | Mild phenotype | Overexpression effects |
| Tg(G298S) | Mutant expression | ALS/FTD phenotype | Variable |

Key Findings from Models

Nuclear depletion is sufficient: NLS mutants cause neurodegeneration
Cell non-autonomous: Glia contribute to motor neuron death
Propagation: Inoculated brain homogenates transmit pathology
Mitochondrial defects: Early energy metabolism changes
Splicing alterations: Dysregulation of critical neuronal transcripts
Therapeutic testing: Models enable drug screening

Other Species

C. elegans: Rapid screening model
Drosophila: Genetic tractability
Zebrafish: Motor neuron development
Non-human primates: Closest to human disease

Model Limitations

Species differences: Mouse models don't fully replicate human disease
Incomplete pathology: Often lack full spectrum of inclusions
Variable expression: Transgene insertion effects
Phenotype variability: Strain background influences

TDP-43 and Cellular Stress

Oxidative Stress Response

TDP-43 plays a role in oxidative stress response:

Direct binding: To oxidative stress response genes
Translation control: Of antioxidant proteins
Mitochondrial ROS: TDP-43 affects mitochondrial function
Therapeutic implications: Antioxidant strategies

Mitochondrial Dynamics

TDP-43 pathology affects mitochondria:

Fragmentation: Altered fission/fusion balance
Transport deficits: Impaired axonal mitochondrial trafficking
Energy failure: ATP production reduction
Mitophagy: Impaired clearance of damaged mitochondria

ER Stress

Endoplasmic reticulum stress is a key pathway:

UPR activation: Unfolded protein response
CHOP expression: Pro-apoptotic signaling
Calcium dysregulation: ER calcium release
Synergy: With other stress pathways

Proteostasis Network

TDP-43 affects protein quality control:

Ubiquitin-proteasome system: Overload in disease
Autophagy-lysosomal pathway: Clearance defects
Molecular chaperones: Hsp90, Hsp70 involvement
Aggregate sequestration: Of degradation machinery

TDP-43 in Glial Cells

Astrocyte Contributions

Astrocytes play a crucial role in TDP-43 pathology:

Reactive gliosis: GFAP upregulation in disease
Secreted factors: Inflammatory cytokines
Neuronal support: Loss of protective functions
Non-cell autonomous: Astrocyte-to-neuron toxicity

Microglial Activation

Microglia contribute to disease progression:

Chronic activation: In ALS/FTD brain
Phagocytic function: May clear or spread pathology
TREM2: Variant affects disease progression
Therapeutic target: Modulation strategies

Oligodendrocyte Involvement

Oligodendrocytes are also affected:

White matter changes: Observed in MRI
Myelin dysfunction: Supporting evidence
Energy support: Metabolic coupling disruption

TDP-43 Propagation Mechanisms

Cell-to-Cell Transmission

TDP-43 can spread between cells:

Mechanisms: Exosomes, tunneling nanotubes, direct transfer
Prion-like: Template-driven aggregation
Neural networks: Anatomical pathways
Therapeutic challenge: Preventing spread

Exosome-Mediated Transfer

Extracellular vesicles carry TDP-43:

Release: From affected neurons
Uptake: By neighboring cells
Seed formation: Initiate aggregation
Detection: In biofluids

Templated Aggregation

Pathological TDP-43 seeds normal protein:

Conformational conversion: Native to pathological
Strain variation: Different conformations
Inheritance: Of aggregation states
Detection: RT-QuIC, PMCA assays

Clinical Features and Diagnosis

ALS Clinical Presentation

Muscle weakness: Progressive, focal onset
Fasciculations: Muscle twitches
Spasticity: Upper motor neuron signs
Respiratory failure: Cause of mortality
Cognitive changes: In ALS/FTD overlap

FTD Clinical Presentation

Behavioral variant: Personality changes
Language variants: Primary progressive aphasia
Motor features: In overlap cases
Disease progression: Variable rate

Diagnostic Criteria

ALS

El Escorial revised: Clinical criteria
Awaji criteria: EMG additions
Gold Coast: Simplified diagnostic criteria

FTD

Rascovsky criteria: Behavioral variant
Neary criteria: Language variants
Biomarker support: Imaging, CSF

Epidemiology

ALS Epidemiology

Incidence: 1-2 per 100,000 annually
Prevalence: 4-6 per 100,000
Age of onset: Median 55-65 years
Sex ratio: Male:female 1.5:1
Sporadic: 90-95% of cases
Familial: 5-10% of cases

FTD Epidemiology

Incidence: 3-4 per 100,000
Prevalence: 10-15 per 100,000
Age of onset: 45-65 years (younger than AD)
Equal sex distribution: No strong gender bias
Subtypes: Variable frequencies

Disease Burden

Healthcare costs: Extremely high per patient
Informal care: Substantial caregiver burden
Lost productivity: Both patients and caregivers
Quality of life: Severe impact on patients and families

Research Funding

Government: NIH, foundations
Industry: Pharmaceutical investments
Patient advocacy: Critical role in awareness

Current Clinical Trials

Active Approaches

| Trial | Agent | Target | Phase |
|-------|-------|--------|-------|
| Various | Antisense oligonucleotides | TARDBP | Pre-clinical |
| Multiple | Small molecule modulators | Aggregation | Phase 1/2 |
| Studies | Cell therapy | Motor neuron replacement | Early phase |
| Trials | Gene therapy | Various | Various |

Challenges in Drug Development

Biomarker development: Need for patient selection
Endpoint validation: Clinical outcome measures
Trial design: Biomarker-driven enrichment
Combination approaches: Likely needed

Conclusion

TDP-43 represents a central pathological protein in ALS and FTD, with implications for understanding disease mechanisms and developing therapies. The protein's normal functions in RNA metabolism, combined with its pathological aggregation, provide multiple therapeutic targets. Despite significant progress in understanding TDP-43 biology, effective disease-modifying treatments remain an urgent unmet need. Future directions include strain-specific therapies, precision medicine approaches, and combination strategies targeting multiple aspects of TDP-43 pathobiology.

References

[Neumann et al., Ubiquitinated TDP-43 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis (2006) (2006)](https://doi.org/10.1126/science.1134108)

[Arai et al., TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis (2006) (2006)](https://doi.org/10.1016/j.bbrc.2006.10.093)

[Unknown, Da Cruz & Cleveland, Understanding the role of TDP-43 in ALS (2011) (2011)](https://doi.org/10.1016/j.neuron.2011.08.015)

[Rutherford et al., TDP-43 mutations in familial and sporadic ALS (2008) (2008)](https://doi.org/10.1126/science.1154584)

[Unknown, Lagier-Tourenne & Cleveland, Rethinking ALS (2009) (2009)](https://doi.org/10.1016/j.cell.2009.09.017)

[Unknown, Baloh RH, TDP-43: the new common thread in neurodegeneration (2011) (2011)](https://doi.org/10.1016/j.tics.2011.08.003)

[Johnson et al., TDP-43 in ALS and FTD (2010) (2010)](https://doi.org/10.1016/j.neuron.2010.11.010)

[Lee et al., Gains or losses in TDP-43-mediated neurodegeneration (2011) (2011)](https://doi.org/10.1038/nrn3120)

[Unknown, Buratti & Baralle, TDP-43: new insights into function (2012) (2012)](https://doi.org/10.1016/j.tics.2012.03.003)

[Unknown, Gitler & Shorter, RNA-binding proteins in neurodegeneration (2017) (2017)](https://doi.org/10.1038/nrn.2017.10)

[Prpar Mihevc et al., TDP-43 pathology in Alzheimer's disease (2019) (2019)](https://doi.org/10.3233/JAD-190565)

[Nelson et al., LATE-NC: a new TDP-43 proteinopathy (2019) (2019)](https://doi.org/10.1093/brain/awz099)

[Mackenzie et al., Nomenclature and consensus for TDP-43 proteinopathies (2010) (2010)](https://doi.org/10.1007/s00401-010-0716-8)

[Brettschneider et al., TDP-43 pathology in ALS (2013) (2013)](https://doi.org/10.1038/nrn3430)

[Rascovsky et al., Diagnostic criteria for FTD (2011) (2011)](https://doi.org/10.1093/brain/awr179)

[Benatar et al., TDP-43 biomarkers for ALS (2018) (2018)](https://doi.org/10.1016/j.neurobiolaging.2018.01.016)

[Feneberg et al., TDP-43 and C9orf72 in ALS/FTD (2018) (2018)](https://doi.org/10.1016/j.tics.2018.07.011)

[Zhang et al., TDP-43 aggregation in neurodegeneration (2019) (2019)](https://doi.org/10.1038/s41582-019-0220-4)

[Smethurst et al., TDP-43 in glial cells (2020) (2020)](https://doi.org/10.1093/brain/awaa164)

[Margeta-Mitrovic et al., TDP-43 and the nucleus (2021) (2021)](https://doi.org/10.1038/s41593-021-00837-1)

[Fernandes et al., TDP-43 post-translational modifications (2022) (2022)](https://doi.org/10.1038/s41582-022-00603-2)

[Calavera et al., TDP-43 strains in disease (2023) (2023)](https://doi.org/10.1016/j.tics.2023.01.004)

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TARDNABINDINGPROTEIN43

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kg_node_id	TARDNABINDINGPROTEIN43
entity_type	protein
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source_table	wiki_pages
wiki_page_id	wp-7093f7dcbe19
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TAR DNA-Binding Protein 43 (TDP-43)

TAR DNA-Binding Protein 43 (TDP-43)

TAR DNA-Binding Protein 43 (TDP-43)

Overview

TAR DNA-Binding Protein 43 (TDP-43)

TAR DNA-Binding Protein 43 (TDP-43)

Overview

Molecular Structure

N-Terminal Domain (residues 1-102)

RNA Recognition Motif 1 (RRM1, residues 106-176)

RNA Recognition Motif 2 (RRM2, residues 191-259)

Glycine-Rich Domain (residues 274-306)

C-Terminal Prion Domain (residues 307-414)

Post-Translational Modifications

Pathological Truncation

Normal Physiological Functions

RNA Processing

Alternative Splicing

RNA Stability and Transport

Transcriptional Regulation

Nuclear-Cytoplasmic Shuttling

Stress Granule Biology

DNA Binding Functions

Pathogenesis in ALS and FTD

TDP-43 Proteinopathy

Loss of Nuclear Function

Toxic Gain-of-Function

Key Disease Mutations

Mechanisms of Neurodegeneration

TDP-43 Strains

TDP-43 in Alzheimer's Disease

LATE-NC

Animal Models

Mouse Models

Key Findings from Models

Therapeutic Strategies

Small Molecule Approaches

Aggregation Inhibitors

Targeting Downstream Pathways

Antisense Oligonucleotides

Gene Therapy Approaches

Immunotherapy

Biomarkers

Cerebrospinal Fluid Biomarkers

Blood Biomarkers

Imaging

Genetics

TARDBP Mutations

Risk Factors

ALS/FTD Genetic Overlap

Neuropathology

Inclusion Types

Regional Distribution

Staging Systems

TDP-43 Interactome

Key Binding Partners

RNA Targets

Future Directions

Emerging Research Areas

Precision Medicine Approaches

Cellular and Animal Models

In Vitro Models

Cell Lines

3D Culture Systems

In Vivo Models

Transgenic Mouse Models

Key Findings from Models

Other Species

Model Limitations

TDP-43 and Cellular Stress

Oxidative Stress Response

Mitochondrial Dynamics

ER Stress

Proteostasis Network

TDP-43 in Glial Cells

Astrocyte Contributions

Microglial Activation

Oligodendrocyte Involvement

TDP-43 Propagation Mechanisms