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

• Published in: International journal of molecular sciences Vol. 22; no. 4; p. 2215
• Main Authors: Cerri, Silvia, Ghezzi, Cristina, Ongari, Gerardo, Croce, Stefania, Avenali, Micol, Zangaglia, Roberta, Di Monte, Donato A, Valente, Enza Maria, Blandini, Fabio
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23-02-2021; MDPI
• Subjects: alpha-synuclein; alpha-Synuclein - metabolism; Autophagy; Biosynthesis; Cell lines; Cells, Cultured; Disease; Enzymes; Extracellular vesicles; Extracellular Vesicles - metabolism; Extracellular Vesicles - pathology; Fibroblasts; Fibroblasts - pathology; GBA mutations; Genotype & phenotype; glucocerebrosidase; Glucosylceramidase; Glucosylceramidase - genetics; Glucosylceramidase - metabolism; Humans; Investigations; Lipids; Molecular modelling; Mutation; Nanoparticles; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson's disease; Pathological effects; Phenotypes; Proteins; Risk analysis; Risk factors; Serine - metabolism; Synuclein; Ultracentrifugation; Vesicles; fibroblasts; lipids; extracellular vesicles; GBA mutations; alpha-synuclein; Parkinson’s disease; glucocerebrosidase
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22042215

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.