# Mechanism and importance of innate immune activation in a Drosophila GBA mutant model of Parkinson's disease

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2021 · $194,375

## Abstract

ABSTRACT:
Mutations in the glucosylceramidase beta (GBA) gene cause the lysosomal lipid storage disorder Gaucher’s
disease and are the most frequent genetic association with Parkinson’s disease and Lewy body dementia.
GBA encodes glucocerebrosidase, a lysosomal enzyme that catalyzes the breakdown of the sphingolipid
glucosylceramide to ceramide and glucose. To explore the mechanism by which mutations in GBA predispose
to these diseases, we created a Drosophila model of glucocerebrosidase deficiency by inactivating the
Drosophila GBA ortholog, Gba1b. Gba1b mutants recapitulate many of the features of these diseases,
including shortened lifespan, locomotor impairment, accumulation of glucosylceramide, protein aggregation
in brain and other tissues, and neurodegeneration. In recently published work, we reported the results of a
proteomic study of Drosophila Gba1b mutants that revealed dramatic alterations in the abundance and
turnover of extracellular vesicle (EV) proteins. Our experiments also demonstrated that these proteomic
findings reflected actual changes in the composition of EVs, and that genetic perturbations targeting factors
involved in the production of EVs suppressed a Gba1b mutant phenotype. In more recent unpublished work,
we used RNA-Seq to compare transcript abundance in Gba1b mutants and controls. This study revealed a
profound induction of the innate immune response pathway in Gba1b mutants. This induction was specific to
Gba1b mutants and was further corroborated in our proteomic data, and RNAi-mediated knockdown of an
innate immune pathway component partially suppressed the brain protein aggregation phenotype of Gba1b
mutants. From these and other findings, we hypothesize that the production of glucosylceramide-enriched
EVs by Gba1b mutants triggers an innate immune response because these EVs resemble the
glucosylceramide-enriched EVs released by pathogens during infection. We further hypothesize that this
innate immune response accounts for the phenotypes of Gba1b mutants. We propose two aims to address
these hypotheses; the first will investigate the mechanism of immune activation, and the second will
investigate the importance of immune activation to Gba1b mutant pathogenesis. Thus, the primary goal of
our research proposal is to provide a foundation for further mechanistic work by asking the two most
fundamental questions raised by our preliminary findings: how does innate immune activation occur in Gba1b
mutants, and is it important to their phenotypes? Given the increasing evidence for neuroinflammation in
neurodegenerative disorders, including those caused by GBA mutations, we anticipate that our work will have
broad medical significance.

## Key facts

- **NIH application ID:** 10259742
- **Project number:** 5R21AG068356-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Leo J Pallanck
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2020-09-10 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259742

## Citation

> US National Institutes of Health, RePORTER application 10259742, Mechanism and importance of innate immune activation in a Drosophila GBA mutant model of Parkinson's disease (5R21AG068356-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10259742. Licensed CC0.

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