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

• Type of Material: Article
• Authors: Seong Su Kang, Emory University; Zhentao Zhang, Emory University; Xia Liu, Emory University; Fredric Manfredsson, Michigan State University; Matthew J. Benskey, Michigan State University; Xuebing Cao, Huazhong University of Science and Technology; Jun Xu, Tongji University; Yi E. Sun, Tongji University; Keqiang Ye, Emory University
• Language: English
• Date: 2017-10-03
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2017, National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1713969114
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 114
• Issue: 40
• Start Page: 10773
• End Page: 10778
• Grant/Funding Information: This work was supported by M. J. FOX Foundation Grant 11137 and NIH Grant RF1, AG051538 (to K.Y.); National Key Basic Research Program of China Grant 2010CB945202 (to Y.E.S.); and NSFC Grants 81461138037, 31471029, and 31671055 (to J.X.).
• Keywords: SUBSTANTIA-NIGRA; Multidisciplinary Sciences; BRAIN; neurodegenerative diseases; substantia nigra; IN-VIVO; MUTATION; RASAGILINE; Science & Technology - Other Topics; EXPRESSION; NEURONS; GROWTH-FACTOR; Lewy bodies; BDNF; Science & Technology; dopamine; ROTATIONAL BEHAVIOR
• Research Categories: Health Sciences, Pathology; Biology, Neuroscience

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 dopamine rgic 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.