Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson's disease

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of nigral dopamine neurons. The deposition of fibrillary aggregated alpha-synuclein in Lewy bodies (LB), that is considered to play a causative role in the disease, constitutes another key neuropathological hallmark of PD. We have recently described that synapsin III (Syn III), a synaptic phosphoprotein that regulates dopamine release in cooperation with alpha-synuclein, is present in the alpha-synuclein insoluble fibrils composing the LB of patients affected by PD. Moreover, we observed that silencing of Syn III gene could prevent alpha-synuclein fibrillary aggregation in vitro. This evidence suggests that Syn III might be crucially involved in alpha-synuclein pathological deposition. To test this hypothesis, we studied whether mice knock-out (ko) for Syn III might be protected from alpha-synuclein aggregation and nigrostriatal neuron degeneration resulting from the unilateral injection of adeno-associated viral vectors (AAV)-mediating human wild-type (wt) alpha-synuclein overexpression (AAV-h alpha syn). We found that Syn III ko mice injected with AAV-h alpha syn did not develop fibrillary insoluble alpha-synuclein aggregates, showed reduced amount of alpha-synuclein oligomers detected by in situ proximity ligation assay (PLA) and lower levels of Ser129-phosphorylated alpha-synuclein. Moreover, the nigrostriatal neurons of Syn III ko mice were protected from both synaptic damage and degeneration triggered by the AAV-h alpha syn injection. Our observations indicate that Syn III constitutes a crucial mediator of alpha-synuclein aggregation and toxicity and identify Syn III as a novel therapeutic target for PD.