Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson's disease-like phenotype

• Published in: Molecular therapy Vol. 30; no. 4; pp. 1465 - 1483
• Main Authors: Faustini, Gaia, Longhena, Francesca, Masato, Anna, Bassareo, Valentina, Frau, Roberto, Klingstedt, Therése, Shirani, Hamid, Brembati, Viviana, Parrella, Edoardo, Vezzoli, Marika, Nilsson, K. Peter R., Pizzi, Marina, Spillantini, Maria Grazia, Bubacco, Luigi, Bellucci, Arianna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.04.2022; American Society of Gene & Cell Therapy
• Subjects: alpha-synuclein; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Dopamine; dopamine release; dopaminergic neurons; Dopaminergic Neurons - metabolism; Gene Silencing; Mice; Mice, Transgenic; motor functions; Original; Parkinson Disease - genetics; Parkinson Disease - therapy; Parkinson's disease; Phenotype; Substantia Nigra - metabolism; synapsin III; Synapsins - genetics; Synapsins - metabolism; synaptic vesicles; motor functions; Parkinson's disease; synapsin III; dopaminergic neurons; dopamine release; alpha-synuclein; synaptic vesicles
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2022.01.021

Fibrillary aggregated α-synuclein (α-syn) deposition in Lewy bodies (LB) characterizes Parkinson's disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with α-syn to regulate dopamine (DA) release and can be found in the insoluble α-syn fibrils composing LB. Moreover, we showed that α-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human α-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates α-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human α-syn transgenic mice at PD-like stage with advanced α-syn aggregation and overt striatal synaptic failure, we could lower α-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates α-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD. [Display omitted] Faustini and colleagues show that the reduction of the neuronal phosphoprotein synapsin III rescues the phenotype observed in the α-synuclein transgenic mice. These findings support that therapeutic strategies targeting synapsin III could be beneficial for the treatment of PD or other synucleinopathies.