TDP-43 aggregation in neurodegeneration: are stress granules the key?
TDP-43 aggregation in neurodegeneration: are stress granules the key?
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DOI：
10.1016/j.brainres.2012.02.032
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发表时间：
2012-06-26
期刊：
影响因子：
2.9
通讯作者：
Yu G
中科院分区：
文献类型：
--
作者：
Dewey CM;Cenik B;Sephton CF;Johnson BA;Herz J;Yu G
RNA结合蛋白TDP-43与神经变性密切相关。不仅编码TDP-43的基因突变与ALS和FTLD相关，而且这种蛋白质也是这些疾病中病理性细胞内包涵体的主要成分。最近的研究大大扩展了我们对TDP-43生理学的理解。目前已知TDP-43在神经元RNA代谢中发挥重要作用。它结合并调节许多RNA编码蛋白质的剪接和稳定性，这些蛋白质参与神经元发育、突触功能和神经变性。因此，这些基本功能的丧失是关于TDP-43在神经变性中的作用的有吸引力的假设。此外，TDP-43是一种易于聚集的蛋白质，鉴于毒性蛋白质聚集体在神经变性中的作用，毒性功能获得机制是另一个合理的假设。重要的是，ALS相关突变调节TDP-43在细胞培养物中聚集的倾向。最近的几项研究已经证明，细胞质TDP-43聚集体与应激颗粒标记物共定位。应激颗粒是细胞质内含物，其在细胞应激时抑制RNA子集的翻译，并且涉及神经变性的几种蛋白质（即Ataxin-2和SMN）与应激颗粒相互作用。因此，理解TDP-43聚集、应激颗粒和ALS相关TDP-43突变的影响之间的相互作用可能是理解TDP-43在神经变性中作用的关键。我们提出了两个模型的TDP-43聚集体的形成。“独立模型”规定TDP-43聚集独立于应激颗粒形成，与“前体模型”相反，“前体模型”提出应激颗粒形成有助于TDP-43聚集“种子”并且慢性应激导致浓度依赖性TDP-43聚集的想法。
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 “independent model” stipulates that TDP-43 aggregation is independent of stress granule formation, in contrast to the “precursor model” which presents the idea that stress granule formation contributes to a TDP-43 aggregate “seed” and that chronic stress leads to concentration-dependent TDP-43 aggregation.
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DOI：
10.1083/jcb.136.4.761
发表时间：
1997-02-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bashkirov VI;Scherthan H;Solinger JA;Buerstedde JM;Heyer WD
通讯作者：
Heyer WD
影响因子：
16.2
作者：
Barbee, Scott A.;Estes, Patricia S.;Ramaswami, Mani
通讯作者：
Ramaswami, Mani
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：
10.5
作者：
Damgaard, Christian Kroun;Lykke-Andersen, Jens
通讯作者：
Lykke-Andersen, Jens
影响因子：
3.3
作者：
Didiot, Marie-Cecile;Subramanian, Murugan;Moine, Herve
通讯作者：
Moine, Herve