ALS10 - Amyotrophic Lateral Sclerosis 10 (TARDBP)

ALS10 - Amyotrophic Lateral Sclerosis 10 (TARDBP)

<div class="infobox infobox-gene">
<div class="infobox-header">ALS10 - TARDBP</div>

Overview

ALS10 - Amyotrophic Lateral Sclerosis 10 (TARDBP)

<div class="infobox infobox-gene">
<div class="infobox-header">ALS10 - TARDBP</div>

Overview

ALS10 (Amyotrophic Lateral Sclerosis 10) is a genetic locus associated with familial amyotrophic lateral sclerosis caused by mutations in the TARDBP gene (TAR DNA-Binding Protein). TARDBP encodes [TDP-43](/mechanisms/tdp-43-proteinopathy), an RNA-binding protein that forms cytoplasmic inclusions in the vast majority of ALS cases and a significant proportion of frontotemporal dementia cases. This protein has become central to understanding the pathogenesis of these devastating neurodegenerative disorders["@neumann2006"][@rutherford2008].

TDP-43 is a highly conserved RNA-binding protein that regulates multiple aspects of RNA metabolism, including transcription, splicing, transport, and translation. The pathological aggregation of TDP-43 in motor neurons and other neuronal populations is a hallmark of ALS and FTLD, making TARDBP/ALS10 one of the most important genetic loci for understanding these diseases.

<div class="infobox-row">
<span class="infobox-label">Gene Symbol</span>
<span class="infobox-value">TARDBP</span>
</div>
<div class="infobox-row">
<span class="infobox-label">Alternative Names</span>
<span class="infobox-value">TDP-43, ALS10, TDP-43 protein</span>
</div>
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<span class="infobox-label">Chromosome</span>
<span class="infobox-value">1p36.22</span>
</div>
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<span class="infobox-label">NCBI Gene ID</span>
<span class="infobox-value">23435</span>
</div>
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<span class="infobox-label">OMIM</span>
<span class="infobox-value">612069</span>
</div>
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<span class="infobox-label">Ensembl ID</span>
<span class="infobox-value">ENSG00000120910</span>
</div>
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<span class="infobox-label">UniProt ID</span>
<span class="infobox-value">Q13148</span>
</div>
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<span class="infobox-label">Protein Length</span>
<span class="infobox-value">414 amino acids</span>
</div>
<div class="infobox-row">
<span class="infobox-label">Gene Type</span>
<span class="infobox-value">Protein coding</span>
</div>
</div>

Gene Overview

| Attribute | Value |
|-----------|-------|
| Gene Symbol | TARDBP |
| Full Name | TAR DNA-Binding Protein |
| Chromosomal Location | 1p36.22 |
| NCBI Gene ID | 23435 |
| OMIM | 612069 |
| Ensembl ID | ENSG00000120910 |
| UniProt ID | Q13148 |
| Protein Length | 414 amino acids |
| Gene Type | Protein coding |

Protein Structure and Function

Domain Architecture

TDP-43 contains distinct structural domains[@buratti2005]:

• N-terminal domain (1-102): Mediates protein-protein interactions and nuclear localization
• RNA recognition motif (RRM1, 102-191): Binds RNA and single-stranded DNA
• RRM2 (191-262): Second RNA-binding domain
• C-terminal domain (262-414): Prion-like region prone to aggregation

RNA Binding Properties

TDP-43 exhibits sequence-nonspecific DNA binding and sequence-specific RNA binding[@polymenidou2011]:

• Binds to UG-rich sequences in RNA
• Recognizes conserved DNA sequences in target genes
• Forms liquid-liquid phase condensates
• Associates with stress granules under stress

Functional Domains

TDP-43 functions in multiple cellular processes:

Role in RNA Metabolism

Transcriptional Regulation

TDP-43 regulates transcription through[@lee2011]:

• Direct binding to gene promoters
• Interaction with transcriptional coactivators
• Chromatin remodeling complex recruitment
• Regulation of transcriptional pause release

RNA Splicing

As an RNA-binding protein, TDP-43 regulates splicing:

| Target | Function | Disease Relevance |
|--------|----------|-------------------|
| CFTR | Exon 9 skipping | Cystic fibrosis models |
| tau (MAPT) | Exon 10 inclusion | AD/FTLD connections |
| ALS genes | Multiple splicing events | Motor neuron disease |

RNA Transport and Localization

TDP-43 participates in:

• Transport of mRNAs to neuronal processes
• Local translation regulation in dendrites
• Synaptic plasticity mechanisms
• Axonal maintenance

Stress Granule Formation

Under cellular stress, TDP-43 localizes to stress granules[@xu2010]:

• Formation of RNA-protein aggregates
• Sequestration of translation machinery
• Protection of mRNAs during stress
• Potential seeding of pathological aggregates

Disease Mechanisms

Pathogenic Mutations

Over 50 mutations in TARDBP have been linked to ALS10[@rutherford2008][@iguchi2013]:

| Mutation | Location | Effect |
|----------|----------|--------|
| A315T | C-terminal | Common, affects aggregation |
| G348C | C-terminal | Nuclear localization defect |
| N352S | C-terminal | Impaired RNA binding |
| M337V | C-terminal | Disrupted protein interactions |
| Q331K | C-terminal | Enhanced aggregation |
| D262G | C-terminal | Alters splicing regulation |

TDP-43 Proteinopathy

The pathological hallmark of ALS10 is TDP-43 proteinopathy[@janssen2019]:

Cytoplasmic inclusions:

• Ubiquitinated cytoplasmic aggregates
• Hyperphosphorylated TDP-43
• C-terminal fragments (CTFs)
• Insoluble protein aggregates

• Loss of nuclear TDP-43
• Impaired nuclear import
• Sequestration in stress granules

• Phosphorylation at Ser409/Ser410
• Ubiquitination
• Sumoylation
• Acetylation

Pathogenesis Cascade

TDP-43 mutations cause ALS through multiple mechanisms:

Implications in Neurodegeneration

Amyotrophic Lateral Sclerosis

ALS10 is central to ALS pathogenesis:

Sporadic ALS: TDP-43 pathology in 95%+ of sporadic ALS Familial ALS: TARDBP mutations account for ~5% of cases Motor neuron degeneration: Selective vulnerability of motor neurons

Frontotemporal Dementia

TDP-43 connects ALS and FTLD[@janssen2019]:

• FTLD-TDP accounts for ~50% of FTLD cases
• Overlapping genetic and pathological features
• Shared mechanisms of protein aggregation
• Common therapeutic targets

Other Neurodegenerative Diseases

Alzheimer's disease: TDP-43 co-pathology in ~30% of AD cases Parkinson's disease: TDP-43 inclusions in some PD cases Huntington's disease: Rare TDP-43 pathology

Neuroinflammation

TDP-43 pathology triggers neuroinflammation[@gao2019]:

Microglial activation:

• Chronic neuroinflammation
• Pro-inflammatory cytokine release
• Phagocytic dysfunction

• Reactive astrogliosis
• Altered glutamate transport
• Impaired metabolic support

Therapeutic Approaches

Current Strategies

Emerging Approaches

• Autophagy enhancers: Promote clearance of aggregates
• Kinase inhibitors: Block pathological phosphorylation
• MicroRNA modulation: Restore normal RNA processing
• Cell replacement: Stem cell-based therapies

Expression Patterns

| Tissue | Expression Level | Notes |
|--------|-----------------|-------|
| Brain | Very high | Neurons, glia |
| Spinal cord | High | Motor neurons |
| Muscle | Low | Skeletal muscle |
| Heart | Moderate | Cardiac tissue |
| Liver | Low | Hepatocytes |

In the nervous system:

• Motor neurons: Highest vulnerability
• Cortical neurons: Affected in FTLD
• Cerebellar neurons: Variable involvement

Research Directions

Unresolved Questions

Emerging Research Areas

• Cryo-EM structures of TDP-43 aggregates
• Single-cell analysis of TDP-43 targets
• iPSC models of TARDBP mutations
• Biomarker development

See Also

• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [TDP-43 Protein](/mechanisms/tdp-43-proteinopathy)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [RNA Metabolism in Neurodegeneration](/mechanisms/rna-metabolism)
• [Protein Aggregation](/mechanisms/protein-aggregation)
• [Motor Neuron Disease](/diseases/motor-neuron-disease)

External Links

• [NCBI Gene: TARDBP](https://www.ncbi.nlm.nih.gov/gene/23435)
• [UniProt: TARDBP](https://www.uniprot.org/uniprot/Q13148)
• [Ensembl: TARDBP](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000120910)
• [OMIM: TARDBP](https://www.omim.org/entry/612069)

Brain Atlas Resources

• [Allen Human Brain Atlas](https://human.brain-map.org/) — gene expression data
• [BrainSpan Atlas](https://brainspan.org/) — developmental transcriptome
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — mouse brain gene expression

References

Pathway Diagram

The following diagram shows the key molecular relationships involving ALS10 - Amyotrophic Lateral Sclerosis 10 (TARDBP) discovered through SciDEX knowledge graph analysis: