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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doaj-52c40c1c184842408f263b511aae77f42021-02-24T00:04:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01222215221510.3390/ijms22042215GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s DiseaseSilvia Cerri0Cristina Ghezzi1Gerardo Ongari2Stefania Croce3Micol Avenali4Roberta Zangaglia5Donato A. Di Monte6Enza Maria Valente7Fabio Blandini8Cellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, 27100 Pavia, ItalyCellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, 27100 Pavia, ItalyCellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, 27100 Pavia, ItalyDepartment of General Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, ItalyDepartment of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, ItalyParkinson’s Disease and Movement Disorders Unit, IRCCS Mondino Foundation, 27100 Pavia, ItalyGerman Centre for Neurodegenerative Diseases (DZNE), 53175 Bonn, GermanyNeurogenetics Research Center, IRCCS Mondino Foundation, 27100 Pavia, ItalyCellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, 27100 Pavia, ItalyHeterozygous 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.https://www.mdpi.com/1422-0067/22/4/2215Parkinson’s diseaseglucocerebrosidaseextracellular vesiclesalpha-synucleinGBA mutationslipids |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Silvia Cerri Cristina Ghezzi Gerardo Ongari Stefania Croce Micol Avenali Roberta Zangaglia Donato A. Di Monte Enza Maria Valente Fabio Blandini |
spellingShingle |
Silvia Cerri Cristina Ghezzi Gerardo Ongari Stefania Croce Micol Avenali Roberta Zangaglia Donato A. Di Monte Enza Maria Valente Fabio Blandini 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 Parkinson’s disease glucocerebrosidase extracellular vesicles alpha-synuclein GBA mutations lipids |
author_facet |
Silvia Cerri Cristina Ghezzi Gerardo Ongari Stefania Croce Micol Avenali Roberta Zangaglia Donato A. Di Monte Enza Maria Valente Fabio Blandini |
author_sort |
Silvia Cerri |
title |
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_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_sort |
gba mutations influence the release and pathological effects of small extracellular vesicles from fibroblasts of patients with parkinson’s disease |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-02-01 |
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. |
topic |
Parkinson’s disease glucocerebrosidase extracellular vesicles alpha-synuclein GBA mutations lipids |
url |
https://www.mdpi.com/1422-0067/22/4/2215 |
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