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Nat Struct Mol Biol. 2017 Aug;24(8):632-642. doi: 10.1038/nsmb.3433. Epub 2017 Jul 3.

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

Author information

1
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
2
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
3
Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA.
4
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
5
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.
6
Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
7
Translational Science and Molecular Medicine, Michigan State University, College of Human Medicine, and Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan, USA.
8
Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, China.
9
Pathophysiology Department, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of the Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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.

PMID:
28671665
PMCID:
PMC5871868
DOI:
10.1038/nsmb.3433
[Indexed for MEDLINE]
Free PMC Article

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