Nature Structural and Molecular Biology
Nature Structural and Molecular Biology
5 years ago

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

Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease
Keqiang Ye, Zhentao Zhang, Yi E Sun, Li He, Jian-Zhi Wang, Duc M Duong, Seong Su Kang, Matthew J Benskey, Xia Liu, Zhaohui Zhang, P Michael Iuvone, Nicholas T Seyfried, Lingjing Jin, Fredric P Manfredsson, Eun Hee Ahn
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.

Publisher URL: http://dx.doi.org/10.1038/nsmb.3433

DOI: 10.1038/nsmb.3433

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