|
Title
|
|
|
|
TARDBP Mutation Analysis in TDP-43 Proteinopathies and Deciphering the Toxicity of Mutant TDP-43
| |
|
Author
|
|
|
|
| |
|
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 similar to 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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Journal of Alzheimer's disease. - -
| |
|
Publication
|
|
|
|
Amsterdam
:
Ios press
,
2013
| |
|
ISSN
|
|
|
|
1387-2877
1875-8908
[Electronic]
| |
|
DOI
|
|
|
|
10.3233/JAD-2012-129036
| |
|
Volume/pages
|
|
|
|
33
:s:[1]
(2013)
, p. S35-S45
| |
|
ISI
|
|
|
|
000314447600005
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|