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, 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[1][2].
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.
| 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 |
TDP-43 contains distinct structural domains[3]:
TDP-43 exhibits sequence-nonspecific DNA binding and sequence-specific RNA binding[4]:
TDP-43 functions in multiple cellular processes:
TDP-43 regulates transcription through[5]:
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 |
TDP-43 participates in:
Under cellular stress, TDP-43 localizes to stress granules[6]:
Over 50 mutations in TARDBP have been linked to ALS10[2:1][7]:
| 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 |
The pathological hallmark of ALS10 is TDP-43 proteinopathy[8]:
Cytoplasmic inclusions:
Nuclear alterations:
Post-translational modifications[9]:
TDP-43 mutations cause ALS through multiple mechanisms:
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
TDP-43 connects ALS and FTLD[8:1]:
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
TDP-43 pathology triggers neuroinflammation[10]:
Microglial activation:
Astrocyte involvement:
| 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:
TDP-43 in ubiquitin-positive inclusions in ALS and FTLD. Neurology. 2006. ↩︎
TARDBP mutations in ALS. Neuron. 2008. ↩︎ ↩︎
TDP-43 binds DNA without sequence specificity. J Biol Chem. 2005. ↩︎
TDP-43 targets conserved DNA sequences. Nat Neurosci. 2011. ↩︎
TDP-43 in RNA splicing. Genes Dev. 2011. ↩︎
TDP-43 and stress granules. J Cell Biol. 2010. ↩︎
TDP-43 in ALS models. J Neurosci. 2013. ↩︎
TDP-43 pathology in ALS/FTD. Acta Neuropathol. 2019. ↩︎ ↩︎
TDP-43 post-translational modifications. Brain Pathol. 2018. ↩︎
TDP-43 in neuroinflammation. Glia. 2019. ↩︎