GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease

Autor: Micol Avenali, Gerardo Ongari, Stefania Croce, Cristina Ghezzi, Silvia Cerri, Donato A. Di Monte, Fabio Blandini, Roberta Zangaglia, Enza Maria Valente
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Parkinson's disease
alpha-synuclein
medicine.disease_cause
genetics [Glucosylceramidase]
lcsh:Chemistry
chemistry.chemical_compound
metabolism [Extracellular Vesicles]
genetics [Parkinson Disease]
Serine
metabolism [alpha-Synuclein]
lcsh:QH301-705.5
Spectroscopy
Cells
Cultured
Mutation
metabolism [Serine]
glucocerebrosidase
Parkinson Disease
General Medicine
Phenotype
Computer Science Applications
Cell biology
medicine.anatomical_structure
ddc:540
Glucosylceramidase
pathology [Fibroblasts]
extracellular vesicles
Article
Catalysis
Inorganic Chemistry
lipids
fibroblasts
pathology [Extracellular Vesicles]
medicine
Humans
metabolism [Glucosylceramidase]
Physical and Theoretical Chemistry
Fibroblast
Molecular Biology
Gene
Alpha-synuclein
Organic Chemistry
medicine.disease
pathology [Parkinson Disease]
chemistry
lcsh:Biology (General)
lcsh:QD1-999
Cell culture
Parkinson’s disease
GBA mutations
Glucocerebrosidase
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 2215, p 2215 (2021)
International journal of molecular sciences 22(4), 2215 (2021). doi:10.3390/ijms22042215
International Journal of Molecular Sciences
Volume 22
Issue 4
ISSN: 1661-6596
1422-0067
DOI: 10.3390/ijms22042215
Popis: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal–lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD.
Databáze: OpenAIRE
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