Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 8, Pages 632-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3433
Keywords
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Funding
- Michael J. Fox Foundation [11137]
- National Natural Science Foundation (NSFC) of China [81571249]
- NSFC [81528007, 81330030]
- National Key Basic Research Program of China [2010CB945202]
- US Public Health Service [P30EY006360, R01EY004864]
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Aggregated forms of alpha-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 alpha-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human alpha-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 alpha-synuclein at N103 in an age-dependent manner. AEP is highly activated in human brains with PD, and it fragments alpha-synuclein, which is found aggregated in Lewy bodies. Overexpression of the AEP-cleaved alpha-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 alpha-synuclein (wild type and A53T mutant) diminishes alpha-synuclein's pathologic effects. Together, these findings support AEP's role as a key mediator of alpha-synuclein-related etiopathological effects in PD.
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