Asparagine endopeptidase cleaves synaptojanin 1 and triggers synaptic dysfunction in Parkinson's disease

Neurobiology of Disease

Zhihao Wang¹  Zhaohui Zhang²  Guiqin Chen³  Min Xiong³  Xingyu Zhang³  Lina Pan³  Lanxia Meng³  Keqiang Ye³  Li Zou³  Ye Tian³  Xin Yuan³  Lihong Bu⁴  Zhentao Zhang⁴  Zhaohui Yao⁵ 

[1] Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA;Department of Geriatrics, 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;PET-CT/MRI Center, Faculty of Radiology and Nuclear Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China;

关键词: AEP;    SYNJ1;    Synaptic dysfunction;    Parkinson's disease;    Neurodegeneration;    α-Synuclein transgenic mice;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown