TDP-43 aggregation in neurodegeneration: Are stress granules the key?

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• 作者：Colleen M. Dewey^a ; Basar Cenik^a ; ^b ; Chantelle F. Sephton^a ; Brett A. Johnson^c ; Joachim Herz^a ; ^b ; Gang Yu^a ; ^{Gang.Yu@UTSouthwestern.edu}
• 关键词：TARDBP ; TDP-43 ; FUS ; Stress granule ; FTD ; FTLD ; Frontotemporal lobar degeneration ; ALS ; Amyotrophic lateral sclerosis ; Neurodegeneration ; Independent model ; Precursor model
• 刊名：Brain Research
• 出版年：2012
• 期刊代码：8_00068993
• 类别：neu
• 出版时间：26 June, 2012
• 卷：1462
• 期：Complete
• 页码：16-25
• 文件大小：789 K

摘要

The RNA-binding protein TDP-43 is strongly linked to neurodegeneration. Not only are mutations in the gene encoding TDP-43 associated with ALS and FTLD, but this protein is also a major constituent of pathological intracellular inclusions in these diseases. Recent studies have significantly expanded our understanding of TDP-43 physiology. TDP-43 is now known to play important roles in neuronal RNA metabolism. It binds to and regulates the splicing and stability of numerous RNAs encoding proteins involved in neuronal development, synaptic function and neurodegeneration. Thus, a loss of these essential functions is an attractive hypothesis regarding the role of TDP-43 in neurodegeneration. Moreover, TDP-43 is an aggregation-prone protein and, given the role of toxic protein aggregates in neurodegeneration, a toxic gain-of-function mechanism is another rational hypothesis. Importantly, ALS related mutations modulate the propensity of TDP-43 to aggregate in cell culture. Several recent studies have documented that cytoplasmic TDP-43 aggregates co-localize with stress granule markers. Stress granules are cytoplasmic inclusions that repress translation of a subset of RNAs in times of cellular stress, and several proteins implicated in neurodegeneration (i.e. Ataxin-2 and SMN) interact with stress granules. Thus, understanding the interplay between TDP-43 aggregation, stress granules and the effect of ALS-associated TDP-43 mutations may be the key to understanding the role of TDP-43 in neurodegeneration. We propose two models of TDP-43 aggregate formation. The 鈥渋ndependent model鈥?stipulates that TDP-43 aggregation is independent of stress granule formation, in contrast to the 鈥減recursor model鈥?which presents the idea that stress granule formation contributes to a TDP-43 aggregate 鈥渟eed鈥?and that chronic stress leads to concentration-dependent TDP-43 aggregation. This article is part of a Special Issue entitled: RNA-Binding Proteins.