Study sheds light on how α-syn triggers neurotoxicity in Parkinson's disease

Alpha-synuclein (α-syn) is a protein highly expressed in the central nervous system. Parkinson's disease (PD) and several other neurodegenerative disorders involve the accumulation of α-syn in neurons in the brain. A large body of evidence suggests that α-syn has a role in the pathophysiology of PD. But the precise mechanisms by which α-syn contributes to neurodegeneration remain unclear.

A study appearing in PNAS now sheds light on this problem. Carried out by researchers from Emory University School of Medicine, Michigan State University, Huazhong University of Science and Technology, and Tongji University School of Medicine, the study demonstrates that α-syn inhibits BDNF/TrkB signaling, leading to the death of dopaminergic neurons. The findings provide an explanation for the loss of dopaminergic neurons in PD patients. Seong Su Kang from Emory University School of Medicine is the first author of the study.

Dopaminergic neurons are a class of neurons that produce dopamine, a neurotransmitter with multiple functions. Progressive loss of dopaminergic neurons is a characteristic of PD and accounts for the motor impairment in PD.

The researchers found that α-syn interacts with TrkB, which is a receptor for BDNF. In other words, α-syn and BDNF compete for dominance over TrkB. BDNF belongs to the neurotrophin family of growth factors that are essential for neuron survival. The researchers discovered that α-syn binds to the kinase domain on TrkB, and this inhibits BDNF/TrkB signaling and therefore leads to dopaminergic neuronal death.

Using mice that overexpressed α-syn, the researchers identified that a metabolite of dopamine -- DOPAL -- stimulates the interaction between α-Syn and TrkB. Moreover, they found that rasagiline, a drug for PD that prevents the breakdown of dopamine, can disrupt α-Syn/TrkB complex and restore TrkB signaling, preventing α-Syn form damaging dopaminergic neurons.

Collectively, the study suggests that α-Syn triggers neurotoxicity in PD through regulation of TrkB neurotrophic activities.

PD is the most frequent age-related motoric neurodegenerative disease. The disease has no cure and current therapies cannot completely treat the symptoms. So it is needed to further explore the pathogenesis of the devastating disease and to develop new therapies based on research findings.
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