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.
(Less)
- author
- Faustini, Gaia
; Longhena, Francesca
; Varanita, Tatiana
; Bubacco, Luigi
; Pizzi, Marina
; Missale, Cristina
; Benfenati, Fabio
; Björklund, Anders
LU
; Spano, Pier Franco
and Bellucci, Arianna
- organization
- publishing date
- 2018-10-01
- 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
- pmid:30046897
- 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
- 2024-06-10 18:16:40
@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}},
keywords = {{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}},
doi = {{10.1007/s00401-018-1892-1}},
volume = {{136}},
year = {{2018}},
}