Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Neurobiol Dis. 2021 Jul;154:105326. doi: 10.1016/j.nbd.2021.105326. Epub 2021 Mar 4.
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which is characterized by the loss of dopaminergic neurons in the nigrostriatal pathway. Synaptic dysfunction impairs dopamine turnover and contributes to the degeneration of dopaminergic neurons. However, the molecular mechanisms underlying synaptic dysfunction and dopaminergic neuronal vulnerability in PD are not clear. Here, we report that synaptojanin 1 (SYNJ1), a polyphosphoinositide phosphatase concentrated at nerve terminals, is a substrate of a cysteine proteinase, asparagine endopeptidase (AEP). SYNJ1 is cleaved by the cysteine proteinase AEP at N599 in the brains of PD patients. AEP-mediated cleavage of SYNJ1 disrupts neuronal phosphoinositide homeostasis and causes synaptic dysfunction. Overexpression of the AEP-generated fragments of SYNJ1 triggers synaptic dysfunction and the degeneration of dopaminergic neurons, inducing motor defects in the α-synuclein transgenic mice. Blockage of AEP-mediated cleavage of SYJN1 alleviates the pathological and behavioral defects in a mouse model of PD. Our results demonstrate that the fragmentation of SYNJ1 by AEP mediates synaptic dysfunction and dopaminergic neuronal degeneration in PD.
帕金森病（PD）是最常见的神经退行性疾病之一，其特征是黑质纹状体通路中的多巴胺能神经元丧失。突触功能障碍会损害多巴胺的周转率，并导致多巴胺能神经元退化。然而，PD 中突触功能障碍和多巴胺能神经元易损性的分子机制尚不清楚。在这里，我们报告说，突触结合蛋白 1（SYNJ1），一种集中在神经末梢的多磷酸肌醇磷酸酶，是半胱氨酸蛋白酶天冬酰胺内肽酶（AEP）的底物。在 PD 患者的大脑中，SYNJ1 在 N599 处被半胱氨酸蛋白酶 AEP 切割。AEP 介导的 SYNJ1 切割破坏了神经元磷酸肌醇稳态并导致突触功能障碍。SYNJ1 的 AEP 生成片段的过表达会引发突触功能障碍和多巴胺能神经元的退化，从而导致α-突触核蛋白转基因小鼠出现运动缺陷。阻断 AEP 介导的 SYJN1 切割可减轻 PD 小鼠模型中的病理和行为缺陷。我们的研究结果表明，AEP 介导的 SYNJ1 片段化在 PD 中介导了突触功能障碍和多巴胺能神经元退化。
