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

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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Funding

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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Correspondence to Arianna Bellucci.

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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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Keywords

  • Syn III
  • α-Synuclein aggregation
  • AAV
  • Nigrostriatal degeneration
  • Synaptic proteins alterations