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.

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Acknowledgements

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. 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.

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Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.

    • Zhentao Zhang
    •  & Zhaohui Zhang
  2. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Zhentao Zhang
    • , Seong Su Kang
    • , Xia Liu
    • , Eun Hee Ahn
    •  & Keqiang Ye
  3. Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Li He
    •  & P Michael Iuvone
  4. Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.

    • P Michael Iuvone
  5. Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Duc M Duong
    •  & Nicholas T Seyfried
  6. Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Duc M Duong
    •  & Nicholas T Seyfried
  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.

    • Matthew J Benskey
    •  & Fredric P Manfredsson
  8. Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, China.

    • Lingjing Jin
    •  & Yi E Sun
  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.

    • Jian-Zhi Wang

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Contributions

K.Y. conceived the project, designed the experiments and wrote the manuscript. Zhentao Zhang designed and performed most of the experiments. S.S.K. and X.L. prepared primary neurons and assisted with animal experiments. M.J.B. and F.P.M. provided clones and packaged viral vectors. D.M.D. and N.T.S. performed the mass spectrometry analysis. L.H. and P.M.I. performed the HPLC experiments and critically read and edited the manuscript. Zhaohui Zhang, E.H.A., L.J., Y.E.S., F.P.M. and J.-Z.W. designed the experiments, assisted with data analysis and interpretation and critically read the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lingjing Jin or Jian-Zhi Wang or Keqiang Ye.

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https://doi.org/10.1038/nsmb.3433