Accumulated α-synuclein affects the progression of GM2 gangliosidoses.
Accumulated α-synuclein affects the progression of GM2 gangliosidoses.
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积累的 α-突触核蛋白影响 GM2 神经节苷脂病的进展。
DOI：
10.1016/j.expneurol.2016.07.011
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发表时间：
2016
影响因子：
5.3
通讯作者：
Hirayasu Y1
中科院分区：
文献类型：
--
作者：
Suzuki K;Yamaguchi A;Yamanaka S;Kanzaki S;Kawashima M;Togo T;Katsuse O;Koumitsu N;Aoki N;Iseki E;Kosaka K;Yamaguchi K;Hashimoto M;Aoki I;Hirayasu Y1
α-突触核蛋白(Asyn)的积聚在几种溶酶体储存疾病(LSD)中已被观察到，但目前尚不清楚Asyn积聚是否参与了LSD的病理过程。桑德霍夫病(SD)患者和SD模型小鼠(Hexb和−/−ASyn+/+小鼠)的神经元中也有ASyn积聚。SD是一种溶酶体储存障碍，是由于β-氨基己糖苷酶A和B上的功能β亚单位缺失，导致神经节苷脂在中枢神经系统内积聚所致。在这里，我们通过建立Hexb、−/−、Asyn和−/−双基因敲除小鼠来探索积聚的Asyn在Hexb Asyn小鼠进展中的作用。我们的结果表明，Hexb、−/−、ASyn和−/−小鼠显示出活跃的小胶质细胞水平和较少的多巴胺能神经元丢失，而不改变神经节苷脂的神经元存储。在Hexb/−/−ASyn+/+小鼠的神经元中，自噬和泛素蛋白酶体通路存在缺陷。在超微结构生理学研究中，线粒体结构看起来退化和功能失调。其结果是，Hexb/−/−ASyn+/+小鼠神经元中锰超氧化物歧化酶2的表达减少，活性氧介导的氧化损伤。有趣的是，这些功能障碍在Hexb、−/−、Asyn和−/−小鼠中得到了改善。但在Hexb、−/−和−/−小鼠中几乎没有观察到任何临床改善。综上所述，这些发现表明ASyn积聚在SD和其他LSD神经病变的发病机制中发挥着重要作用，因此是新疗法的靶点。
The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb −/− ASyn +/+mice). SD is a lysosomal storage disorder caused by the absence of a functional β-subunit on the β-hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression ofHexb−/− mice by creating aHexb −/− ASyn −/−double-knockout mice. Our results show thatHexb −/− ASyn −/−mice demonstrated active microglia levels and less dopaminergic neuron loss, without altering the neuronal storage of ganglioside. The autophagy and ubiquitin proteasome pathways are defective in the neurons ofHexb −/− ASyn +/+mice. In ultrastructural physiological studies, the mitochondria structures look degenerated and dysfunctional. As a result, expression of manganese superoxide dismutase 2 are reduced, and reactive oxygen species-mediated oxidative damage in the neurons ofHexb −/− ASyn +/+mice. Interestingly, these dysfunctions improved inHexb −/− ASyn −/−mice. But any clinical improvement were hardly observed inHexb −/− ASyn −/−mice.Taken together, these findings suggest that ASyn accumulation plays an important role in the pathogenesis of neuropathy in SD and other LSDs, and is therefore a target for novel therapies.