@inbook{db40097d6e114fcbbdfada9010a31dfe,
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.",
keywords = "Amyotrophic lateral sclerosis, TARDBP, TDP-43, frontotemporal lobar degeneration, mutation, neurodegeneration",
author = "Gendron, {Tania F.} and Rosa Rademakers and Leonard Petrucelli",
year = "2012",
doi = "10.3233/978-1-61499-154-0-35",
language = "English (US)",
isbn = "9781614991533",
series = "Advances in Alzheimer's Disease",
pages = "35--45",
editor = "George Perry and Xiongwei Zhu and Mark Smith and Aaron Sorensen and Jesus Avila",
booktitle = "Alzheimer'S Disease",
}