Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles

Autoři: Kathryn A. Jewett aff001;  Ruth E. Thomas aff001;  Chi Q. Phan aff001;  Bernice Lin aff003;  Gillian Milstein aff001;  Selina Yu aff001;  Lisa F. Bettcher aff004;  Fausto Carnevale Neto aff004;  Danijel Djukovic aff004;  Daniel Raftery aff004;  Leo J. Pallanck aff001;  Marie Y. Davis aff003
Působiště autorů: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America aff001;  Department of Biology, Juniata College, Huntingdon, Pennsylvania, United States of America aff002;  VA Puget Sound Healthcare System, Seattle, Washington, United States of America aff003;  Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America aff004;  Department of Neurology, University of Washington, Seattle, Washington, United States of America aff005
Vyšlo v časopise: Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles. PLoS Genet 17(2): e1008859. doi:10.1371/journal.pgen.1008859
Kategorie: Research Article


Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson’s disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations in glucosidase, beta acid 1 (GBA), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster disease progression. To explore how GBA mutations influence pathogenesis, we previously created a Drosophila model of GBA deficiency (Gba1b) that manifests neurodegeneration and accelerated protein aggregation. Proteomic analysis of Gba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from Gba1b mutants. Accordingly, we hypothesized that GBA may influence pathogenic protein aggregate spread via EVs. We found that accumulation of ubiquitinated proteins and Ref(2)P, Drosophila homologue of mammalian p62, were reduced in muscle and brain tissue of Gba1b flies by ectopic expression of wildtype GCase in muscle. Neuronal GCase expression also rescued protein aggregation both cell-autonomously in brain and non-cell-autonomously in muscle. Muscle-specific GBA expression reduced the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from Gba1b flies. Perturbing EV biogenesis through neutral sphingomyelinase (nSMase), an enzyme important for EV release and ceramide metabolism, enhanced protein aggregation when knocked down in muscle, but did not modify Gba1b mutant protein aggregation when knocked down in neurons. Lipidomic analysis of nSMase knockdown on ceramide and glucosylceramide levels suggested that Gba1b mutant protein aggregation may depend on relative depletion of specific ceramide species often enriched in EVs. Finally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency promotes accelerated protein aggregate spread between cells and tissues via dysregulated EVs, and EV-mediated trafficking of GCase may partially account for the reduction in aggregate spread.

Klíčová slova:

Actins – Biosynthesis – Drosophila melanogaster – Muscle proteins – Muscle tissue – Parkinson disease – Protein aggregation – principal component analysis


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