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

by Kathryn A. Jewett, Ruth E. Thomas, Chi Q. Phan, Bernice Lin, Gillian Milstein, Selina Yu, Lisa F. Bettcher, Fausto Carnevale Neto, Danijel Djukovic, Daniel Raftery, Leo J. Pallanck, Marie Y. Davis 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 inglucosidase,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 howGBA mutations influence pathogenesis, we previously created aDrosophila model ofGBA deficiency (Gba1b) that manifests neurodegeneration and accelerated protein aggregation. Proteomic analysis ofGba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs fromGba1b mutants. Accordingly, we hypothesized thatGBA 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 ofGba1b 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-specificGBA expression reduced the eleva...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research