α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 27, 2016 (received for review November 10, 2016)
January 17, 2017
114 (5) 1183-1188

Significance

We discovered that α-synuclein interacts with the neuroprotective protein phosphoinositide-3 kinase enhancer L (PIKE-L) in an S129 phosphorylation-dependent manner and sequesters PIKE-L in Lewy bodies, leading to the hyperactivation of AMP-activated protein kinase (AMPK) and subsequent dopaminergic neuronal cell death. Our findings may identify a molecular mechanism by which α-synuclein triggers dopaminergic neuronal cell death in Parkinson’s disease.

Abstract

The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson’s disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds α-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP+), whereas PIKE-L knockdown elevates α-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or α-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that α-synuclein neutralizes PIKE-L’s neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK.

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Acknowledgments

We thank Dr. Zhijun Luo at Boston University for the lentivirus construct of dominant-negative AMPK. This work was supported by Grant 11137 from the Michael J. Fox Foundation (to K.Y.).

Supporting Information

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 114 | No. 5
January 31, 2017
PubMed: 28096359

Classifications

Submission history

Published online: January 17, 2017
Published in issue: January 31, 2017

Keywords

  1. neurodegenerative disease
  2. dopamine
  3. Lewy bodies

Acknowledgments

We thank Dr. Zhijun Luo at Boston University for the lentivirus construct of dominant-negative AMPK. This work was supported by Grant 11137 from the Michael J. Fox Foundation (to K.Y.).

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Seong Su Kang
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
Zhentao Zhang
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
Xia Liu
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
Fredric P. Manfredsson
Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503;
Li He
Department of Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, GA 30322;
P. Michael Iuvone
Department of Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, GA 30322;
Xuebing Cao
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
Yi E. Sun
Translational Center for Stem Cell Research, Tongji Hospital, Shanghai 200065, China;
Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China;
Lingjing Jin1 [email protected]
Department of Neurology, Tongji Hospital, Shanghai 200065, China
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
Translational Center for Stem Cell Research, Tongji Hospital, Shanghai 200065, China;
Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China;

Notes

1
To whom correspondence may be addressed. Email: [email protected] or [email protected].
Author contributions: S.S.K., Z.Z., L.J., and K.Y. designed research; S.S.K., Z.Z., and X.L. performed research; F.P.M., L.H., and P.M.I. contributed new reagents/analytic tools; X.C., Y.E.S., and L.J. analyzed data; and K.Y. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation
    Proceedings of the National Academy of Sciences
    • Vol. 114
    • No. 5
    • pp. 783-E905

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