Function Of TAR DNA-binding Protein 43 Research Articles

TDP‐43 A315T mutation in familial motor neuron disease

To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA-binding protein 43 (TDP-43) proteinopathies to investigate TDP-43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP-43 gene led to the identification of a novel missense mutation, Ala-315-Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration.

TDP-43 proteinopathies: a new class of proteinopathies

The recent identification of TAR-DNA-binding protein-43 (TDP-43) as the major component of the pathologic inclusions characteristic to sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), as well as most forms of amyotrophic lateral sclerosis (ALS), resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein in these conditions and provides further evidence that ALS and FTLD-U represent a clinicopathological spectrum of neurodegenerative disorders that share similar pathomechanisms. Although the physiological function of TDP-43 in the brain and its specific role in FTLD-U and ALS pathogenesis is currently unknown, the presence of ubiquitinated, hyperphosphorylated and truncated species of TDP-43, in addition to redistribution of physiological TDP-43 from the nucleus to cytoplasmic inclusions, implicates TDP-43 in a novel and unifying mechanism of neurodegeneration in TDP-43 proteinopathies. In this review, we summarize the identification of TDP-43 and the advances in understanding TDP-43 proteinopathies, and finally we discuss the implications of these discoveries for future strategies in developing diagnostics and therapeutics for FTLD-U and ALS.