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

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