title: Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration.
abstract: Mutations in the glucosidase, beta, acid (GBA1) gene cause Gaucher's disease, and are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) excluding variants of low penetrance. Because α-synuclein-containing neuronal aggregates are a defining feature of PD and DLB, it is widely believed that mutations in GBA1 act by enhancing α-synuclein toxicity. To explore this hypothesis, we deleted the Drosophila GBA1 homolog, dGBA1b, and compared the phenotypes of dGBA1b mutants in the presence and absence of α-synuclein expression. Homozygous dGBA1b mutants exhibit shortened lifespan, locomotor and memory deficits, neurodegeneration, and dramatically increased accumulation of ubiquitinated protein aggregates that are normally degraded through an autophagic mechanism. Ectopic expression of human α-synuclein in dGBA1b mutants resulted in a mild enhancement of dopaminergic neuron loss and increased α-synuclein aggregation relative to controls. However, α-synuclein expression did not substantially enhance other dGBA1b mutant phenotypes. Our findings indicate that dGBA1b plays an important role in the metabolism of protein aggregates, but that the deleterious consequences of mutations in dGBA1b are largely independent of α-synuclein. Future work with dGBA1b mutants should reveal the mechanism by which mutations in dGBA1b lead to accumulation of protein aggregates, and the potential influence of this protein aggregation on neuronal integrity.
authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington, United States of America.|Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Marie Y
authors.initials: MY
authors.lastname: Davis
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kien
authors.initials: K
authors.lastname: Trinh
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Thomas
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Selina
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Germanos
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Whitley
authors.affiliation: Neuroscience, Rare Diseases Research Unit, Sanofi Genzyme, Framingham, Massachusetts, United States of America.
authors.forename: Sergio Pablo
authors.initials: SP
authors.lastname: Sardi
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Pallanck
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D004331:Drosophila melanogaster; D005776:Gaucher Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D066263:Protein Aggregation, Pathological; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051844:alpha-Synuclein; D005962:Glucosylceramidase