| Literature DB >> 28671665 |
Zhentao Zhang1,2, Seong Su Kang2, Xia Liu2, Eun Hee Ahn2, Zhaohui Zhang1, Li He3, P Michael Iuvone3,4, Duc M Duong5,6, Nicholas T Seyfried5,6, Matthew J Benskey7, Fredric P Manfredsson7, Lingjing Jin8, Yi E Sun8, Jian-Zhi Wang9, Keqiang Ye2.
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-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.Entities:
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Year: 2017 PMID： 28671665 PMCID： PMC5871868 DOI： 10.1038/nsmb.3433
Source DB: PubMed Journal: Nat Struct Mol Biol ISSN： 1545-9985 Impact factor: 15.369