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Acta Neuropathol. 2018 Oct;136(4):621-639. doi: 10.1007/s00401-018-1892-1. Epub 2018 Jul 25.

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

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Division of Pharmacology, Department of molecular and Translational Medicine, University of Brescia, Viale Europa no. 11, 25123, Brescia, Italy.
Department of Biology, University of Padova, Via Ugo Bassi 58b, 35121, Padua, Italy.
Center for Synaptic Neuroscience and Technology, Italian Institute of Technology, Via Morego, 30, 16163, Genoa, Italy.
IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy.
Neurobiology Unit, BMC A11, Department of Experimental Medical Science, Lund University, 221 84, Lund, Sweden.
Division of Pharmacology, Department of molecular and Translational Medicine, University of Brescia, Viale Europa no. 11, 25123, Brescia, Italy.
Laboratory for Preventive and Personalized Medicine, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.


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.


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


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