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Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 24, 2017 (received for review August 7, 2017)
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.
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.
Alpha-synuclein binds and inhibits TrkB receptors
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