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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

Faustini, Gaia; Longhena, Francesca; Varanita, Tatiana; Bubacco, Luigi; Pizzi, Marina; Missale, Cristina; Benfenati, Fabio; Björklund, Anders LU ; Spano, Pier Franco and Bellucci, Arianna (2018) In Acta Neuropathologica 136(4). p.621-639
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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AAV, Nigrostriatal degeneration, Syn III, Synaptic proteins alterations, α-Synuclein aggregation
in
Acta Neuropathologica
volume
136
issue
4
pages
19 pages
publisher
Springer
external identifiers
  • scopus:85050690070
ISSN
0001-6322
DOI
10.1007/s00401-018-1892-1
language
English
LU publication?
yes
id
0e9ab7fd-47ca-4e1b-ace6-f900bee5dc7a
date added to LUP
2018-10-01 13:00:18
date last changed
2019-08-14 04:23:36
@article{0e9ab7fd-47ca-4e1b-ace6-f900bee5dc7a,
  abstract     = {<p>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.</p>},
  author       = {Faustini, Gaia and Longhena, Francesca and Varanita, Tatiana and Bubacco, Luigi and Pizzi, Marina and Missale, Cristina and Benfenati, Fabio and Björklund, Anders and Spano, Pier Franco and Bellucci, Arianna},
  issn         = {0001-6322},
  keyword      = {AAV,Nigrostriatal degeneration,Syn III,Synaptic proteins alterations,α-Synuclein aggregation},
  language     = {eng},
  month        = {10},
  number       = {4},
  pages        = {621--639},
  publisher    = {Springer},
  series       = {Acta Neuropathologica},
  title        = {Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease},
  url          = {http://dx.doi.org/10.1007/s00401-018-1892-1},
  volume       = {136},
  year         = {2018},
}