ArticleProceedings of the National Academy of Sciences of the United States of America2017
TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers, 1 of them a synthesis that pooled it.
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Who cites it
82 citing papers in PubMed, 1 synthesis or guideline pooled it, 127 citations in OpenAlex.
- Health Benefits of Endurance Training: Implications of the Brain-Derived Neurotrophic Factor-A Systematic Review.Neural plasticity · 2019Pooled it
- Targeting receptor tyrosine kinases: from molecular mechanisms to clinical therapeutics.Signal transduction and targeted therapy · 2026Review
- Inhibition of Abnormal Elevated α-Synuclein Ameliorates Dopaminergic Neuron Degeneration in Parkinson's Disease Mouse Model.Aging cell · 2026Article
- Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Targeting the BDNF/TrkB/CREB pathway: emerging strategies for neuroprotection in Parkinson's disease.Molecular biology reports · 2026Review
- ASL/ALT Ratio in Familial and Sporadic Parkinson's Disease: Insights From Cross-Sectional Logistic Analysis.Brain and behavior · 2026Article
- Unravelling the novel insights between miR-7 and Parkinson's disease (PD).Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Review
- BDNF-amyloid-Frontiers in molecular neuroscience · 2026Review
- Therapeutic potential of exerkines in neurodegenerative and mental disorders: a narrative review.Frontiers in physiology · 2026Review
- ALDH2 protects against dopaminergic neuronal cell ferroptosis by enhancing the enzyme activity of PRDX6 in Parkinson's disease.NPJ Parkinson's disease · 2025Article
- The Intricate Relationship of Trk Receptors in Brain Diseases and Disorders.Molecular neurobiology · 2025Review
- LRRK2 and the fragile synapse: a molecular prelude to Parkinson's disease?The Biochemical journal · 2025Review
- Alpha-synuclein Fibrils Inhibit Activation of the BDNF/ERK Signaling Loop in the mPFC to Induce Parkinson's Disease-like Alterations with Depression.Neuroscience bulletin · 2025Article
- Article
- Disruption of axonal transport in Parkinson's disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling.NPJ Parkinson's disease · 2025Article
- Enhancing sleep quality in synucleinopathies through physical exercise.Frontiers in cellular neuroscience · 2025Review
- Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Exercise as a multitarget therapy: modulating myokines, neurotrophins, and inflammation in Parkinson's disease.Frontiers in aging neuroscience · 2025Review
- Neuroanatomical mapping of huntingtin-associated protein 1 across the rostral and caudal clusters of mouse raphe nuclei and its immunohistochemical relationships with serotonin.Frontiers in neuroanatomy · 2025Article
- Harnessing BDNF Signaling to Promote Resilience in Aging.Aging and disease · 2024Review
22 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
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.
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