Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease
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.
Nature Structural and Molecular Biology
Digital Object Identifier (DOI)
Zhang, Zhentao; Kang, Seong Su; Liu, Xia; Ahn, Eun Hee; Zhang, Zhaohui; He, Li; Iuvone, P. Michael; Duong, Duc M.; Seyfried, Nicholas T.; Benskey, Matthew J.; Manfredsson, Fredric P.; Jin, Lingjing; Sun, Yi E.; Wang, Jian Zhi; and Ye, Keqiang, "Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease" (2017). Translational Neuroscience. 1405.