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Author Notes:

Correspondence should be addressed to K.Y. (kye@emory.edu), L.J. (lingjingjin@13.com) or J.-Z.W. (wangjz@mails.tjmu.edu.cn).

See publication for full list of author contributions.

We thank the ADRC at Emory University for providing human PD, LBD and healthy-control samples, and C. Watts (University of Cambridge) for providing anti-AEP.

The authors declare no competing financial interests.


Research Funding:

This work was supported by grants from the Michael J. Fox Foundation (grant ID 11137) to K.Y.; a grant from the National Natural Science Foundation (NSFC) of China (no. 81571249) to Zhentao Zhang; NSFC grant (no. 81528007) to K.Y. and J.-Z.W.; a National Key Basic Research Program of China grant (2010CB945202) to Y.E.S.; an NSFC grant (81330030) to Y.E.S.; and grants from the US Public Health Service (P30EY006360 and R01EY004864) to P.M.I.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Biophysics
  • Cell Biology
  • MICE

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

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Journal Title:

Nature Structural and Molecular Biology


Volume 24, Number 8


, Pages 632-+

Type of Work:

Article | Post-print: After Peer Review


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.

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© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

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