Glucocerebrosidase deficiency promotes protein aggregation through dysregulation of extracellular vesicles.
PLoS Genet
; 14(9): e1007694, 2018 09.
Article
em En
| MEDLINE
| ID: mdl-30256786
ABSTRACT
Mutations in the glucosylceramidase beta (GBA) gene are strongly associated with neurodegenerative diseases marked by protein aggregation. GBA encodes the lysosomal enzyme glucocerebrosidase, which breaks down glucosylceramide. A common explanation for the link between GBA mutations and protein aggregation is that lysosomal accumulation of glucosylceramide causes impaired autophagy. We tested this hypothesis directly by measuring protein turnover and abundance in Drosophila mutants with deletions in the GBA ortholog Gba1b. Proteomic analyses revealed that known autophagy substrates, which had severely impaired turnover in autophagy-deficient Atg7 mutants, showed little to no overall slowing of turnover or increase in abundance in Gba1b mutants. Likewise, Gba1b mutants did not have the marked impairment of mitochondrial protein turnover seen in mitophagy-deficient parkin mutants. Proteasome activity, microautophagy, and endocytic degradation also appeared unaffected in Gba1b mutants. However, we found striking changes in the turnover and abundance of proteins associated with extracellular vesicles (EVs), which have been proposed as vehicles for the spread of protein aggregates in neurodegenerative disease. These changes were specific to Gba1b mutants and did not represent an acceleration of normal aging. Western blotting of isolated EVs confirmed the increased abundance of EV proteins in Gba1b mutants, and nanoparticle tracking analysis revealed that Gba1b mutants had six times as many EVs as controls. Genetic perturbations of EV production in Gba1b mutants suppressed protein aggregation, demonstrating that the increase in EV abundance contributed to the accumulation of protein aggregates. Together, our findings indicate that glucocerebrosidase deficiency causes pathogenic changes in EV metabolism and may promote the spread of protein aggregates through extracellular vesicles.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
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Proteínas de Drosophila
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Agregação Patológica de Proteínas
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Vesículas Extracelulares
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Glucosilceramidase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
PLoS Genet
Assunto da revista:
GENETICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos