Abstract
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 α-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 α-synuclein, is present in the α-synuclein insoluble fibrils composing the LB of patients affected by PD. Moreover, we observed that silencing of Syn III gene could prevent α-synuclein fibrillary aggregation in vitro. This evidence suggests that Syn III might be crucially involved in α-synuclein pathological deposition. To test this hypothesis, we studied whether mice knock-out (ko) for Syn III might be protected from α-synuclein aggregation and nigrostriatal neuron degeneration resulting from the unilateral injection of adeno-associated viral vectors (AAV)-mediating human wild-type (wt) α-synuclein overexpression (AAV-hαsyn). We found that Syn III ko mice injected with AAV-hαsyn did not develop fibrillary insoluble α-synuclein aggregates, showed reduced amount of α-synuclein oligomers detected by in situ proximity ligation assay (PLA) and lower levels of Ser129-phosphorylated α-synuclein. Moreover, the nigrostriatal neurons of Syn III ko mice were protected from both synaptic damage and degeneration triggered by the AAV-hαsyn injection. Our observations indicate that Syn III constitutes a crucial mediator of α-synuclein aggregation and toxicity and identify Syn III as a novel therapeutic target for PD.
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This work was supported by the Michael J. Fox Foundation USA Target Advancement Program, Grant ID #10742.
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Conceptualization GF, PS and AB; Methodology, GF, FL, TV and AB; Investigation, GF, FL, TV, LB and AB; Writing-original draft, GF, PS and AB; Writing-review and editing, GF, LB, MP, CM, FB, AnB, and AB; Funding Acquisition, AB; Resources, LB, FB, AnB and AB; Supervision, AnB, AB.
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Faustini, G., Longhena, F., Varanita, T. et al. Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease. Acta Neuropathol 136, 621–639 (2018). https://doi.org/10.1007/s00401-018-1892-1
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DOI: https://doi.org/10.1007/s00401-018-1892-1