# Metabolo-Genetic Dissection of GBA and Lysosomal Genes in Parkinson's Disease and Lewy Body Dementia

> **NIH NIH R21** · BAYLOR COLLEGE OF MEDICINE · 2021 · $200,000

## Abstract

Synucleinopathies, including Lewy body dementia (LBD) and Parkinson’s disease (PD), are common and
incurable neurodegenerative disorders with strong evidence for heritability. Loss-of-function variants in
Glucocerebrosidase (GBA) cause Gaucher’s disease, a recessive lysosomal storage disorder (LSD). It is
estimated that 85% or greater loss of Glucocerebrosidase activity is required to trigger Gaucher’s.
Paradoxically however, heterozygous carriers of GBA variants—causing modest reductions in overall enzyme
function—have a significantly increased risk of PD and LBD, and GBA alleles also dominantly modify risk of
dementia among subjects with PD. Emerging evidence suggests that GBA loss of function may enhance the
neurotoxicity of α-synuclein (αSyn), the pathological protein that aggregates to form brain Lewy bodies in PD
and LBD. However, the mechanism by which partial reduction in GBA activity contributes to pathogenesis of
synucleinopathy remains elusive. Since most GBA variant carriers do not develop disease in their lifetimes,
other factors likely contribute to disease penetrance. In an exome-wide study, we discovered an aggregate
genetic variant burden among 54 LSD genes associated with PD risk. In fact, over half of subjects carried at
least one variant, and 21% carried 2 or more variants. These results suggest that (i) other LSD genes likely
contribute to synucleinopathy, and (ii) LSD gene variants may interact with one another to modify risk and
progression of neurodegeneration. In this proposal we test the hypothesis that partial, haploinsufficient
loss of function in LSD genes disrupts sphingolipid metabolism, leading to enhanced lysosomal stress
and increased vulnerability to αSyn-induced, age-dependent neurodegeneration. In compelling
preliminary studies, we have performed comprehensive genetic manipulations of 94 conserved homologs of
human LSD genes in a Drosophila transgenic model of αSyn-mediated neurodegeneration, identifying GBA
and 17 other candidate enhancers. A preponderance of modifiers are implicated in lysosomal metabolism of
ceramide and sphingolipids. Here, we will employ the powerful and rapid genetics available in Drosophila to
systematically confirm interactions between LSD genes and αSyn-mediated neurodegeneration <Aim 1a> and
assess impact on αSyn protein dynamics <Aim 1b>. To establish clinical relevance, LSD gene modifiers of
αSyn will be examined for associations with PD/LBD pathology in human brain autopsy cohorts <Aim 1c>. In
parallel, the most promising LSD gene modifiers of αSyn will be interrogated for impact on lysosomal structure
and function <Aim 2a>, and we will perform mass-spectrometry to profile sphingolipid perturbations in a GBA
allelic series with graduated reduction in Glucocerebrosidase activity <Aim 2b>. In sum, this exploratory
project will establish a causal chain between partial loss-of-function in GBA and other LSD genes leading to
subclinical derangements in lysosomal metabolism, αSyn neuropa...

## Key facts

- **NIH application ID:** 10223187
- **Project number:** 5R21AG068961-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Joshua M Shulman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $200,000
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223187

## Citation

> US National Institutes of Health, RePORTER application 10223187, Metabolo-Genetic Dissection of GBA and Lysosomal Genes in Parkinson's Disease and Lewy Body Dementia (5R21AG068961-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10223187. Licensed CC0.

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