Abstract
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.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting 1–2% of people over 65 years of age [1]
Parkinson’s disease (PD) is a common neurodegenerative disease characterized by abnormal clumps of proteins within the brain and other tissues which can lead to cellular dysfunction and death
We found that restoring GCase protein in the muscle of mutant flies reduced protein aggregation in muscle and the brain, suggesting a mechanism involving interaction between tissues
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting 1–2% of people over 65 years of age [1]. The stereotypic spread of Lewy bodies in PD from the rostral brain stem to the midbrain and eventually throughout the neocortex suggests a prion-like mechanism mediating propagation of protein aggregates from neuron to neuron [5]. This temporo-spatial spread of Lewy bodies correlates with clinical progression of PD and has been replicated in several animal models [6,7,8]. Much work has focused on identifying genes involved in PD, and how perturbation of these genes lead to PD pathogenesis, the mechanisms underlying PD are not yet completely understood
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