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

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 muta...

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Autores principales: Cerri, Silvia, Ghezzi, Cristina, Ongari, Gerardo, Croce, Stefania, Avenali, Micol, Zangaglia, Roberta, Di Monte, Donato A., Valente, Enza Maria, Blandini, Fabio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927041/
https://www.ncbi.nlm.nih.gov/pubmed/33672321
http://dx.doi.org/10.3390/ijms22042215
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author Cerri, Silvia
Ghezzi, Cristina
Ongari, Gerardo
Croce, Stefania
Avenali, Micol
Zangaglia, Roberta
Di Monte, Donato A.
Valente, Enza Maria
Blandini, Fabio
author_facet Cerri, Silvia
Ghezzi, Cristina
Ongari, Gerardo
Croce, Stefania
Avenali, Micol
Zangaglia, Roberta
Di Monte, Donato A.
Valente, Enza Maria
Blandini, Fabio
author_sort Cerri, Silvia
collection PubMed
description 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.
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spelling pubmed-79270412021-03-04 GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease Cerri, Silvia Ghezzi, Cristina Ongari, Gerardo Croce, Stefania Avenali, Micol Zangaglia, Roberta Di Monte, Donato A. Valente, Enza Maria Blandini, Fabio Int J Mol Sci Article 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. MDPI 2021-02-23 /pmc/articles/PMC7927041/ /pubmed/33672321 http://dx.doi.org/10.3390/ijms22042215 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cerri, Silvia
Ghezzi, Cristina
Ongari, Gerardo
Croce, Stefania
Avenali, Micol
Zangaglia, Roberta
Di Monte, Donato A.
Valente, Enza Maria
Blandini, Fabio
GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease
title GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease
title_full GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease
title_fullStr GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease
title_full_unstemmed GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease
title_short GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease
title_sort gba mutations influence the release and pathological effects of small extracellular vesicles from fibroblasts of patients with parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927041/
https://www.ncbi.nlm.nih.gov/pubmed/33672321
http://dx.doi.org/10.3390/ijms22042215
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