ALS10 - Amyotrophic Lateral Sclerosis 10 (TARDBP)
<div class="infobox infobox-gene">
<div class="infobox-header">ALS10 - TARDBP</div>
Overview
Mermaid diagram (expand to render)
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>
<div class="infobox-row">
<span class="infobox-label">Chromosome</span>
<span class="infobox-value">1p36.22</span>
</div>
<div class="infobox-row">
<span class="infobox-label">NCBI Gene ID</span>
<span class="infobox-value">23435</span>
</div>
<div class="infobox-row">
<span class="infobox-label">OMIM</span>
<span class="infobox-value">612069</span>
</div>
<div class="infobox-row">
<span class="infobox-label">Ensembl ID</span>
<span class="infobox-value">ENSG00000120910</span>
</div>
<div class="infobox-row">
<span class="infobox-label">UniProt ID</span>
<span class="infobox-value">Q13148</span>
</div>
<div class="infobox-row">
<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:
Transcription regulation: Modulates gene expression
RNA splicing: Regulates alternative splicing events
RNA transport: Facilitates mRNA localization
Translation control: Regulates translation initiation and elongation
Stress response: Forms stress granulesTranscriptional 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
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
Nuclear alterations:
- Loss of nuclear TDP-43
- Impaired nuclear import
- Sequestration in stress granules
Post-translational modifications[@chen2018]:
- Phosphorylation at Ser409/Ser410
- Ubiquitination
- Sumoylation
- Acetylation
Pathogenesis Cascade
TDP-43 mutations cause ALS through multiple mechanisms:
Loss of nuclear function: Impaired RNA processing
Gain of toxicity: Cytoplasmic aggregation
RNA metabolism disruption: Aberrant splicing
Mitochondrial dysfunction: Altered energy metabolism
Stress granule persistence: Chronic cellular stressImplications 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
Astrocyte involvement:
- Reactive astrogliosis
- Altered glutamate transport
- Impaired metabolic support
Therapeutic Approaches
Current Strategies
Anti-aggregation drugs: Small molecules preventing TDP-43 aggregation
RNA-based therapies: ASOs targeting mutant TARDBP transcripts
Gene therapy: Viral delivery of wild-type TDP-43
Protein stabilizers: Compounds stabilizing native structureEmerging 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
What triggers initial TDP-43 aggregation?
How do specific mutations lead to disease?
What determines cell-type vulnerability?
Can TDP-43 pathology be reversed?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
[Neumann M et al., TDP-43 in ubiquitin-positive inclusions in ALS and FTLD, Neurology (2006)](https://pubmed.ncbi.nlm.nih.gov/17030756/)
[Rutherford NJ et al., TARDBP mutations in ALS, Neuron (2008)](https://pubmed.ncbi.nlm.nih.gov/18794197/)
[Buratti E et al., TDP-43 binds DNA without sequence specificity, J Biol Chem (2005)](https://pubmed.ncbi.nlm.nih.gov/15888398/)
[Ayala YM et al., TDP-43 in mitochondrial function, Hum Mol Genet (2008)](https://pubmed.ncbi.nlm.nih.gov/18728632/)
[Iguchi Y et al., TDP-43 in ALS models, J Neurosci (2013)](https://pubmed.ncbi.nlm.nih.gov/23946415/)
[Janssen C et al., TDP-43 pathology in ALS/FTD, Acta Neuropathol (2019)](https://pubmed.ncbi.nlm.nih.gov/31049891/)
[Polymenidou M et al., TDP-43 targets conserved DNA sequences, Nat Neurosci (2011)](https://pubmed.ncbi.nlm.nih.gov/21940628/)
[Lee EB et al., TDP-43 in RNA splicing, Genes Dev (2011)](https://pubmed.ncbi.nlm.nih.gov/21940784/)Pathway Diagram
The following diagram shows the key molecular relationships involving ALS10 - Amyotrophic Lateral Sclerosis 10 (TARDBP) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)