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Brain-Derived Extracellular Vesicles in Health and Disease: A Methodological Perspective
Open AccessArticle

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

1
Cellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy
2
Department of General Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
3
Department of Clinical, Surgical, Diagnostic & Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
4
Department of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, Italy
5
Neurorehabilitation Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy
6
Parkinson’s Disease and Movement Disorders Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy
7
German Centre for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany
8
Neurogenetics Research Center, IRCCS Mondino Foundation, 27100 Pavia, Italy
9
Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Leonora Balaj
Int. J. Mol. Sci. 2021, 22(4), 2215; https://doi.org/10.3390/ijms22042215
Received: 6 January 2021 / Revised: 15 February 2021 / Accepted: 20 February 2021 / Published: 23 February 2021
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. View Full-Text
Keywords: Parkinson’s disease; glucocerebrosidase; extracellular vesicles; alpha-synuclein; GBA mutations; lipids; fibroblasts Parkinson’s disease; glucocerebrosidase; extracellular vesicles; alpha-synuclein; GBA mutations; lipids; fibroblasts
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MDPI and ACS Style

Cerri, S.; Ghezzi, C.; Ongari, G.; Croce, S.; Avenali, M.; Zangaglia, R.; Di Monte, D.A.; Valente, E.M.; Blandini, F. GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease. Int. J. Mol. Sci. 2021, 22, 2215. https://doi.org/10.3390/ijms22042215

AMA Style

Cerri S, Ghezzi C, Ongari G, Croce S, Avenali M, Zangaglia R, Di Monte DA, Valente EM, Blandini F. GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease. International Journal of Molecular Sciences. 2021; 22(4):2215. https://doi.org/10.3390/ijms22042215

Chicago/Turabian Style

Cerri, Silvia; Ghezzi, Cristina; Ongari, Gerardo; Croce, Stefania; Avenali, Micol; Zangaglia, Roberta; Di Monte, Donato A.; Valente, Enza M.; Blandini, Fabio. 2021. "GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease" Int. J. Mol. Sci. 22, no. 4: 2215. https://doi.org/10.3390/ijms22042215

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