Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease.
Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease.
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DOI：
10.1038/nsmb.3433
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发表时间：
2017-08
影响因子：
16.8
通讯作者：
Ye K
中科院分区：
文献类型：
--
作者：
Zhang Z;Kang SS;Liu X;Ahn EH;Zhang Z;He L;Iuvone PM;Duong DM;Seyfried NT;Benskey MJ;Manfredsson FP;Jin L;Sun YE;Wang JZ;Ye K
α-突触核蛋白的聚集形式在突触核蛋白病如帕金森病（PD）的发病机制中起关键作用。然而，α-突触核蛋白致病作用的分子机制尚未完全了解。在这里，我们表明，天冬酰胺内肽酶（AEP）切割人α-突触核蛋白，触发其聚集和升级其神经毒性，从而导致多巴胺能神经元的损失和运动障碍的小鼠模型。AEP被激活并以年龄依赖性方式在N103处切割人α-突触核蛋白。AEP在患有PD的人脑中高度活化，并且它使α-突触核蛋白片段化，发现α-突触核蛋白聚集在路易体中。黑质中AEP切割的α-突触核蛋白1 -103片段的过表达诱导小鼠多巴胺能神经元损失和运动缺陷。相反，抑制AEP介导的α-突触核蛋白（野生型和A53 T突变体）的切割减少了α-突触核蛋白的病理作用。总之，这些发现支持AEP作为PD中α-突触核蛋白相关的病因病理学作用的关键介导物的作用。
Aggregated forms of α-synuclein play a crucial role in the pathogenesis of synucleinopathies such as Parkinson’s disease (PD). However, the molecular mechanisms underlying the pathogenic effects of α-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human α-synuclein, triggers its aggregation and escalates its neurotoxicity, thus leading to dopaminergic neuronal loss and motor impairments in a mouse model. AEP is activated and cleaves human α-synuclein at N103 in an age-dependent manner. AEP is highly activated in human brains with PD, and it fragments α-synuclein, which is found aggregated in Lewy bodies. Overexpression of the AEP-cleaved α-synuclein1–103 fragment in the substantia nigra induces both dopaminergic neuronal loss and movement defects in mice. In contrast, inhibition of AEP-mediated cleavage of α-synuclein (wild type and A53T mutant) diminishes α-synuclein’s pathologic effects. Together, these findings support AEP’s role as a key mediator of α-synuclein-related etiopathological effects in PD.
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DOI：
10.1073/pnas.132197599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Lee, MK;Stirling, W;Price, DL
通讯作者：
Price, DL
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
4.8
作者：
Liu, CW;Giasson, BI;Thomas, PJ
通讯作者：
Thomas, PJ
影响因子：
2.9
作者：
Mishizen-Eberz, AJ;Norris, EH;Lynch, DR
通讯作者：
Lynch, DR