Does a loss of TDP-43 function cause neurodegeneration?
Does a loss of TDP-43 function cause neurodegeneration?
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DOI：
10.1186/1750-1326-7-27
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发表时间：
2012-06-14
影响因子：
15.1
通讯作者：
Xu ZS
中科院分区：
文献类型：
--
作者：
Xu ZS
In 2006, TAR-DNA binding protein 43 kDa (TDP-43) was discovered to be in the intracellular aggregates in the degenerating cells in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two fatal neurodegenerative diseases [1,2]. ALS causes motor neuron degeneration leading to paralysis [3,4]. FTLD causes neuronal degeneration in the frontal and temporal cortices leading to personality changes and a loss of executive function [5]. The discovery triggered a flurry of research activity that led to the discovery of TDP-43 mutations in ALS patients and the widespread presence of TDP-43 aggregates in numerous neurodegenerative diseases. A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the striking neurodegenerative phenotypes in numerous TDP-43-overexpression models. In this review, I will draw attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominant-negative effect on the wild-type TDP-43 allele. Furthermore, I will discuss how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, review the literature in model systems to discuss how the current data support the loss-of-function mechanism and highlight some key questions for testing this hypothesis in the future.
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DOI：
10.1111/j.1440-1789.2009.01091.x
发表时间：
2010-04
期刊：
Neuropathology : official journal of the Japanese Society of Neuropathology
影响因子：
--
作者：
Geser F;Lee VM;Trojanowski JQ
通讯作者：
Trojanowski JQ
影响因子：
30.8
作者：
Farrer MJ;Hulihan MM;Kachergus JM;Dächsel JC;Stoessl AJ;Grantier LL;Calne S;Calne DB;Lechevalier B;Chapon F;Tsuboi Y;Yamada T;Gutmann L;Elibol B;Bhatia KP;Wider C;Vilariño-Güell C;Ross OA;Brown LA;Castanedes-Casey M;Dickson DW;Wszolek ZK
通讯作者：
Wszolek ZK
影响因子：
3.5
作者：
Ash, Peter E. A.;Zhang, Yong-Jie;Link, Christopher D.
通讯作者：
Link, Christopher D.
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.
影响因子：
12.7
作者：
Brandmeir, Nicholas J.;Geser, Felix;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.