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Research Article

TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

Seong Su Kang, Zhentao Zhang, Xia Liu, View ORCID ProfileFredric P. Manfredsson, Matthew J. Benskey, Xuebing Cao, Jun Xu, Yi E. Sun, and Keqiang Ye
  1. aDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
  2. bDepartment of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China;
  3. cTranslational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503;
  4. dDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
  5. eEast Hospital, Tongji University School of Medicine, Shanghai 200120, China;
  6. fTranslational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
  7. gDepartment of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China

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PNAS first published September 18, 2017; https://doi.org/10.1073/pnas.1713969114
Seong Su Kang
aDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
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Zhentao Zhang
aDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
bDepartment of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China;
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Xia Liu
aDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
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Fredric P. Manfredsson
cTranslational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503;
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  • ORCID record for Fredric P. Manfredsson
Matthew J. Benskey
cTranslational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503;
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Xuebing Cao
dDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
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Jun Xu
eEast Hospital, Tongji University School of Medicine, Shanghai 200120, China;
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  • For correspondence: xunymc2000@yahoo.com kye@emory.edu
Yi E. Sun
fTranslational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
gDepartment of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China
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Keqiang Ye
aDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
fTranslational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
gDepartment of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China
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  • For correspondence: xunymc2000@yahoo.com kye@emory.edu
  1. Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 24, 2017 (received for review August 7, 2017)

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Significance

Alpha-synuclein plays an important role in the pathophysiology of Parkinson’s disease (PD), however the molecular mechanisms related to α-synuclein in neurodegeneration of PD remain unknown. We show that α-synuclein specifically inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. The disruption of this interaction rescues TrkB signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. This study reveals the mechanism related to α-synuclein–induced neurotoxicity of PD via regulation of TrkB neurotrophic signaling.

Abstract

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

  • neurodegenerative diseases
  • dopamine
  • Lewy bodies
  • substantia nigra

Footnotes

  • ↵1To whom correspondence may be addressed. Email: xunymc2000{at}yahoo.com or kye{at}emory.edu.
  • Author contributions: S.S.K., Z.Z., J.X., and K.Y. designed research; S.S.K., Z.Z., and X.L. performed research; F.P.M., M.J.B., X.C., and Y.E.S. contributed new reagents/analytic tools; S.S.K., J.X., and K.Y. analyzed data; and J.X. and K.Y. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1713969114/-/DCSupplemental.

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Alpha-synuclein binds and inhibits TrkB receptors
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P. Manfredsson, Matthew J. Benskey, Xuebing Cao, Jun Xu, Yi E. Sun, Keqiang Ye
Proceedings of the National Academy of Sciences Sep 2017, 201713969; DOI: 10.1073/pnas.1713969114

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Alpha-synuclein binds and inhibits TrkB receptors
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P. Manfredsson, Matthew J. Benskey, Xuebing Cao, Jun Xu, Yi E. Sun, Keqiang Ye
Proceedings of the National Academy of Sciences Sep 2017, 201713969; DOI: 10.1073/pnas.1713969114
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