Rabphilin-3A as a novel target to reverse α-synuclein-induced synaptic loss in Parkinson's disease

Toxic aggregates of alpha-synuclein (alpha syn) are considered key drivers of Parkinson's disease (PD) pathology. In early PD, alpha syn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying alpha syn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract alpha syn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with alpha syn and involved in stabilizing dendritic spines and in promoting the synaptic retention of NMDA-type glutamate receptors. We found that in vivo intrastriatal injection of alpha syn-preformed fibrils in mice induces the early loss of striatal synapses associated with decreased synaptic levels of Rph3A and impaired Rph3A/NMDA receptors interaction. Modulating Rph3A striatal expression or interfering with the Rph3A/alpha syn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in alpha syn-injected mice. Notably, the same experimental approaches prevented alpha syn-induced synaptic loss in vitro in primary hippocampal neurons. Overall, these findings indicate that approaches aimed at restoring Rph3A synaptic functions can slow down the early synaptic detrimental effects of alpha syn aggregates in PD.