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

TY - JOUR

T1 - Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease

AU - Faustini, Gaia

AU - Longhena, Francesca

AU - Varanita, Tatiana

AU - Bubacco, Luigi

AU - Pizzi, Marina

AU - Missale, Cristina

AU - Benfenati, Fabio

AU - Björklund, Anders

AU - Spano, Pier Franco

AU - Bellucci, Arianna

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - AAV

KW - Nigrostriatal degeneration

KW - Syn III

KW - Synaptic proteins alterations

KW - α-Synuclein aggregation

U2 - 10.1007/s00401-018-1892-1

DO - 10.1007/s00401-018-1892-1

M3 - Article

C2 - 30046897

AN - SCOPUS:85050690070

VL - 136

SP - 621

EP - 639

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 1432-0533

IS - 4

ER -