title: TARDBP mutation analysis in TDP-43 proteinopathies and deciphering the toxicity of mutant TDP-43.
abstract: The identification of TAR DNA-binding protein 43 (TDP-43) as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions has defined a new class of neurodegenerative conditions: the TDP-43 proteinopathies. This breakthrough was quickly followed by mutation analysis of TARDBP, the gene encoding TDP-43. Herein, we provide a review of our previously published efforts that led to the identification of 3 TARDBP mutations (p.M337V, p.N345K, and p.I383V) in familial ALS patients, two of which were novel. With over 40 TARDBP mutations now discovered, there exists conclusive evidence that TDP-43 plays a direct role in neurodegeneration. The onus is now on researchers to elucidate the mechanisms by which mutant TDP-43 confers toxicity, and to exploit these findings to gain a better understanding of how TDP-43 contributes to the pathogenesis of disease. Our biochemical analysis of TDP-43 in ALS patient lymphoblastoid cell lines revealed a substantial increase in TDP-43 truncation products, including a ≈ 25 kDa fragment, compared to control lymphoblastoid cell lines. We discuss the putative harmful consequence of abnormal TDP-43 fragmentation, as well as highlight additional mechanisms of toxicity associated with mutant TDP-43.
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Tania F
authors: TF
authors: Gendron
authors: Rosa
authors: R
authors: Rademakers
authors: Leonard
authors: L
authors: Petrucelli
mesh_terms: D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D009154:Mutation; D057177:TDP-43 Proteinopathies / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins