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Alterations in lipid metabolism modify GBA1-mediated neurodegeneration in a Drosophila model of Parkinson’s disease

M. Davis, R. Thomas, A. Germanos, S. Yu, B. Whitley, L. Pallanck (Seattle, WA, USA)

Meeting: 2017 International Congress

Abstract Number: 1063

Keywords: Lipid metabolism, Lysosomal disorders, Parkinsonism

Session Information

Date: Wednesday, June 7, 2017

Session Title: Parkinson's Disease: Genetics

Session Time: 1:15pm-2:45pm

Location: Exhibit Hall C

Objective: To understand how glucocerebrosidase (GBA1) mutations increase susceptibility to Parkinson’s disease (PD).

Background: Our understanding of the pathogenesis PD remains limited, and currently no disease-modifying therapies exist. Mutations in GBA1 are the strongest genetic risk factor for PD, and GBA1 encodes glucocerebrosidase, an important enzyme in lipid metabolism. However, most GBA1 carriers do not develop PD, suggesting the presence of modifiers. To investigate how GBA1 influences PD pathogenesis, we created a Drosophila model of GBA1 deficiency (GBA1del) that has neurodegeneration and impaired lysosomal protein degradation (Davis, et al.).

Methods: A pilot screen using our GBA1del model was conducted to identify genetic modifiers. Chromosomal deletions were screened for suppression or enhancement of the climbing deficit present in GBA1del homozygotes compared to controls. The modifier locus was identified by narrowing candidate regions using publicly available smaller overlapping deletions and mutated alleles. Modifiers were further characterized by enhancement/suppression of other GBA1del phenotypes, including impairment in autophagy. Targeted lipidomic analysis was used to evaluate alterations in lipid metabolism due to genetic perturbations of modifiers in GBA1del  mutants.

Results: Eleven chromosomal deletions were identified as modifiers. Glucosylceramide transferase (GlcT-1), which encodes an enzyme with the reverse enzymatic activity to GBA1, was identified as a modifying locus.  A publicly available mutation of GlcT-1 suppressed accelerated insoluble protein aggregation in GBA1del homozygotes. Ectopic expression of GlcT-1 enhanced the climbing deficit, increased insoluble ubiquitinated protein aggregation, and shortened lifespan of GBA1del homozygotes.

Conclusions: GlcT-1 is a modifier of GBA1-mediated pathogenesis in Drosophila. Loss of function of GlcT-1 suppresses GBA1 mutant phenotypes, and is predicted to increase ceramide and decrease glucosylceramide levels, suggesting that decreased levels of ceramide and/or increased levels of glucosylceramide may lead to neurodegeneration in GBA1del homozygotes. Further studies characterizing modifiers, including targeted lipidomics, will elucidate whether alterations in lipid metabolite levels are responsible for the pathogenic mechanisms causing PD and may reveal new targets for disease-modifying therapies in PD.

References: Davis MY, Trinh K, Thomas RE, Yu S, Germanos AA, Whitley B, Sardi SP, Montine TJ. Glucocerebrosidase deficiency in Drosophila results in α-synuclein-independent protein aggregation and neurodegeneration. PLoS Genetics, 2016; 12(3):e1005944.

To cite this abstract in AMA style:

M. Davis, R. Thomas, A. Germanos, S. Yu, B. Whitley, L. Pallanck. Alterations in lipid metabolism modify GBA1-mediated neurodegeneration in a Drosophila model of Parkinson’s disease [abstract]. Mov Disord. 2017; 32 (suppl 2). https://www.mdsabstracts.org/abstract/alterations-in-lipid-metabolism-modify-gba1-mediated-neurodegeneration-in-a-drosophila-model-of-parkinsons-disease/. Accessed May 20, 2025.
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