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

• Published in: Pharmacological research Vol. 183; p. 106375
• Main Authors: Ferrari, Elena, Scheggia, Diego, Zianni, Elisa, Italia, Maria, Brumana, Marta, Palazzolo, Luca, Parravicini, Chiara, Pilotto, Andrea, Padovani, Alessandro, Marcello, Elena, Eberini, Ivano, Calabresi, Paolo, Diluca, Monica, Gardoni, Fabrizio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.09.2022; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; alpha-Synuclein - metabolism; Animals; Dendritic spines; Mice; Nerve Tissue Proteins; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson’s disease; Protein-protein interactions; Rabphilin-3A; Receptors, N-Methyl-D-Aspartate - metabolism; Vesicular Transport Proteins - metabolism; α-synuclein; Rabphilin-3A; PLA; LTP; Rph3A; GFP; SPN; BSA; Dendritic spines; OD; αsyn; dpi; α-synuclein; SNpc; DAPI; AMPAR; Protein-protein interactions; DIV; TIF; TH; DAT; SIM; NMDAR; Mice; αsyn-PFF; LTD; Parkinson’s disease
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2022.106375

Toxic aggregates of α-synuclein (αsyn) are considered key drivers of Parkinson’s disease (PD) pathology. In early PD, αsyn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying αsyn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract αsyn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with αsyn 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 αsyn-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/αsyn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in αsyn-injected mice. Notably, the same experimental approaches prevented αsyn-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 αsyn aggregates in PD. [Display omitted] •αsyn-PFF induces in vivo and in vitro early loss of striatal dendritic spines.•αsyn-PFF induces in vivo and in vitro alterations of Rph3A/NMDAR complex.•Rph3A overexpression improves motor behavior in the αsyn-PFF mice model.•Rph3A is novel molecular target to counteract αsyn-induced synaptic failure.