Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson’s disease

• Type of Material: Article
• Authors: Zhentao Zhang, Emory University; Seong Su Kang, Emory University; Xia Liu, Emory University; Eun Hee Ahn, Emory University; Zhaohui Zhang, Renmin Hospital of Wuhan University; Li He, Emory University; P Michael Iuvone, Emory University; Duc M. Duong, Emory University; Nicholas Seyfried, Emory University; Matthew J. Benskey, Michigan State University; Fredric P. Manfredsson, Michigan State University; Lingjing Jin, Tongji University; Yi E. Sun, Tongji University; Jian-Zhi Wang, Huazhong University of Science & Technology; Keqiang Ye, Emory University
• Language: English
• Date: 2017-08-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nsmb.3433
• Title of Journal or Parent Work: Nature Structural and Molecular Biology
• ISSN: 1545-9993
• Volume: 24
• Issue: 8
• Start Page: 632
• End Page: +
• Grant/Funding Information: This work was supported by grants from the Michael J. Fox Foundation (grant ID 11137) to K.Y.; a grant from the National Natural Science Foundation (NSFC) of China (no. 81571249) to Zhentao Zhang; NSFC grant (no. 81528007) to K.Y. and J.-Z.W.; a National Key Basic Research Program of China grant (2010CB945202) to Y.E.S.; an NSFC grant (81330030) to Y.E.S.; and grants from the US Public Health Service (P30EY006360 and R01EY004864) to P.M.I.
• Keywords: MUTATION; LEGUMAIN; AGGREGATION; Biophysics; Cell Biology; ALZHEIMERS-DISEASE; ANIMAL-MODELS; MICE; Biochemistry & Molecular Biology; CATHEPSIN-D; Life Sciences & Biomedicine; Science & Technology; IN-VITRO; PROTEIN; DEGRADATION
• Research Categories: Health Sciences, Pathology; Chemistry, Biochemistry; Biology, Neuroscience

Abstract

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-synuclein 1-103 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.