Functional Study of SNCA p.V15A Variant: Further Linking α-Synuclein and Glucocerebrosidase.
Parkinson's disease
SNCA gene
functional characterization
glucocerebrosidase
α-synuclein
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
04 Mar 2024
04 Mar 2024
Historique:
revised:
16
12
2023
received:
20
06
2023
accepted:
22
01
2024
medline:
4
3
2024
pubmed:
4
3
2024
entrez:
4
3
2024
Statut:
aheadofprint
Résumé
SNCA p.V15A was reported in five families. In vitro models showed increased aggregation and seeding activity, mitochondrial damage, and apoptosis. Mutant flies had reduced flying ability and survival. To clinically and functionally evaluate SNCA p.V15A in a large Italian family with Parkinson's disease (PD). Genetic diagnosis was reached through next-generation sequencing. Pathogenicity was assessed by molecular dynamics simulation and biochemical studies on peripheral blood mononuclear cells (PBMCs). Five siblings carried SNCA p.V15A; three developed bradykinetic-rigid PD in their 50s with rapid motor progression and variable cognitive impairment. A fourth sibling had isolated mood disturbance, whereas the fifth was still unaffected at age 47. The mutant protein showed decreased stability and an unstable folded structure. Proband's PBMCs showed elevated total and phosphorylated α-synuclein (α-syn) levels and significantly reduced glucocerebrosidase activity. This study demonstrates accumulation of α-syn
Sections du résumé
BACKGROUND
BACKGROUND
SNCA p.V15A was reported in five families. In vitro models showed increased aggregation and seeding activity, mitochondrial damage, and apoptosis. Mutant flies had reduced flying ability and survival.
OBJECTIVES
OBJECTIVE
To clinically and functionally evaluate SNCA p.V15A in a large Italian family with Parkinson's disease (PD).
METHODS
METHODS
Genetic diagnosis was reached through next-generation sequencing. Pathogenicity was assessed by molecular dynamics simulation and biochemical studies on peripheral blood mononuclear cells (PBMCs).
RESULTS
RESULTS
Five siblings carried SNCA p.V15A; three developed bradykinetic-rigid PD in their 50s with rapid motor progression and variable cognitive impairment. A fourth sibling had isolated mood disturbance, whereas the fifth was still unaffected at age 47. The mutant protein showed decreased stability and an unstable folded structure. Proband's PBMCs showed elevated total and phosphorylated α-synuclein (α-syn) levels and significantly reduced glucocerebrosidase activity.
CONCLUSION
CONCLUSIONS
This study demonstrates accumulation of α-syn
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Fondazione Cariplo project 2017-0575
Organisme : Ministero della Salute Ricerca Corrente 2022-2024
Organisme : NEXTGENERATIONEU (NGEU)
Organisme : Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS
ID : PE0000006
Organisme : A Multiscale integrated approach to the study of the nervous system in health and disease
ID : DN. 1553 11.10.2022
Informations de copyright
© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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