What is the role of the TAR DNA-binding protein gene (TARDBP) in the pathophysiology of amyotrophic lateral sclerosis (ALS)?

Updated: Jun 14, 2018
  • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD, MHCM, CPE, FAAPL  more...
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Answer

In 2006, ubiquitinated inclusions containing pathologic forms of TAR DNA-binding protein-43 (TDP-43) were identified in the cytoplasm of motor neurons of patients with sporadic ALS and in a subset of patients with frontotemporal dementia. [35, 36] TDP-43 is an RNA-processing protein that is normally localized predominantly in the nucleus.

Shortly after their identification in sporadic ALS, TDP-43–positive cytoplasmic inclusions were identified in patients with non-SOD1 familial ALS [37, 38] , and mutations in the gene on chromosome 1 coding for TDP-43 were identified in patients with sporadic and familial ALS. [39, 40, 41, 42, 43, 44]

Mutations in the TARDBP gene, which codes for TDP-43, account for 5% of patients with familial ALS. In addition, TDP-43 inclusions have been found in more than 90% of patients with sporadic ALS, in patients with Guamanian parkinsonism-dementia complex, [45] in the majority of patients with frontotemporal dementia, and in patients with familial British dementia. [46] A review of the continuum of multisystem TDP-43 proteinopathies concluded that the phenotypic expression is linked to the specific cells that are affected by the proteinopathy. [47]


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