The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation.
The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation.
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DOI：
10.1186/s40478-016-0402-8
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发表时间：
2016-12-09
影响因子：
7.1
通讯作者：
Outeiro TF
中科院分区：
文献类型：
--
作者：
Lázaro DF;Dias MC;Carija A;Navarro S;Madaleno CS;Tenreiro S;Ventura S;Outeiro TF
α-突触核蛋白（aSyn）与散发性和家族性帕金森病（PD）有关，帕金森病是仅次于阿尔茨海默病的第二大常见神经退行性疾病。特别是，编码aSyn的基因的增殖和点突变会导致家族性PD。此外，在PD、路易体痴呆或多系统萎缩等疾病中，在路易体和路易神经突中aSyn的积累表明，aSyn错误折叠和聚集在这些疾病中起着重要作用，这些疾病统称为突触核蛋白病。aSyn的确切功能尚不清楚，但已知它与囊泡和膜有关，并影响重要的细胞功能，如细胞内运输和蛋白质降解系统，导致细胞病理，可以很容易地在基于细胞的模型中研究。因此，了解aSyn点突变的分子效应可能为了解疾病发病的分子机制提供重要的见解。我们研究了最近发现的A53E aSyn突变的影响。结合体外研究和细胞模型研究，我们发现这种突变减少了aSyn聚集，增加了蛋白酶体活性，改变了正常的蛋白酶平衡。我们观察到，在我们的实验范式中，A53E突变影响了aSyn聚集过程的特定步骤和不同的细胞过程，为突触核蛋白病的分子机制提供了新的思路。本文的在线版本（doi:10.1186/s40478-016-0402-8）包含补充材料，可供授权用户使用。
α-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies. The exact function of aSyn remains unclear, but it is known to be associated with vesicles and membranes, and to have an impact on important cellular functions such as intracellular trafficking and protein degradation systems, leading to cellular pathologies that can be readily studied in cell-based models. Thus, understanding the molecular effects of aSyn point mutations may provide important insight into the molecular mechanisms underlying disease onset. We investigated the effect of the recently identified A53E aSyn mutation. Combining in vitro studies with studies in cell models, we found that this mutation reduces aSyn aggregation and increases proteasome activity, altering normal proteostasis. We observed that, in our experimental paradigms, the A53E mutation affects specific steps of the aggregation process of aSyn and different cellular processes, providing novel ideas about the molecular mechanisms involved in synucleinopathies. The online version of this article (doi:10.1186/s40478-016-0402-8) contains supplementary material, which is available to authorized users.
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影响因子：
8.6
作者：
Appel-Cresswell, Silke;Vilarino-Guell, Carles;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
9.8
作者：
Chartier-Harlin, Marie-Christine;Dachsel, Justus C.;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
影响因子：
168.9
作者：
Ibáñez, P;Bonnet, AM;Brice, A
通讯作者：
Brice, A
影响因子：
4.8
作者：
Dikiy, Igor;Eliezer, David
通讯作者：
Eliezer, David