Gba mutations influence the release and pathological effects of small extracellular vesicles from fibroblasts of patients with parkinson’s disease

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Abstract

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocere-brosidase (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.

Original languageEnglish
Article number2215
Pages (from-to)1-12
Number of pages12
JournalInternational Journal of Molecular Sciences
Volume22
Issue number4
DOIs
Publication statusPublished - Feb 2 2021

Keywords

  • Alpha-synuclein
  • Extracellular vesicles
  • Fibroblasts
  • GBA mutations
  • Glucocerebrosidase
  • Lipids
  • Parkinson’s disease

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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