# INTERACTIONS BETWEEN LYSOSOMAL STORAGE DISORDER GENES, SPHINGOLIPID HOMEOSTASIS, AND ALPHA-SYNUCLEIN MECHANISMS IN PARKINSON'S DISEASE

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2021 · $39,636

## Abstract

Project Summary
Parkinson’s disease (PD) is an incurable neurodegenerative disorder with strong evidence for
heritability. The heterozygous presence of variants in glucocerebrosidase (GBA) increases PD
risk by five-fold compared to non-carriers. However, the mechanism by which the partial loss of
glucocerebrosidase function contributes to PD susceptibility is unknown. Complete loss of
glucocerebrosidase function results in Gaucher’s disease, one of 54 rare autosomal recessive
or X-linked diseases known as lysosomal storage disorders (LSDs). Recently work from my
laboratory showed that burden of LSD gene variants significantly associated with PD risk, even
to the exclusion of GBA, indicating that LSD genes in addition to GBA may contribute to the
onset of PD pathogenesis. Interestingly, several of the implicated genes function within a shared
sphingolipid metabolism pathway, similar to GBA. For my project, I will use Drosophila to
investigate the hypothesis that partial or haploinsufficient loss of LSD gene function disrupts
sphingolipid metabolism, leading to enhanced lysosomal stress and increased vulnerability to
PD-related stressors such as α-synuclein toxicity and aging. My project take advantage of my
preliminary data, in which I screened over 300 transgenic Drosophila lines to identify 21 LSD
genes whose knockdown enhanced α-synuclein toxicity. I will confirm the mechanism of
enhancement to determine how partial loss of these LSD genes might contribute to PD
susceptibility. My project also addresses the role of partial gene loss in PD by using different
strengths of GBA loss of function mutants. I will analyze these mutants for the dose-dependent
disruption of sphingolipid metabolism using mass spectrometry-based lipidomics, before
attempting to further perturb sphingolipid metabolism with other LSD genes to modify
neurodegeneration. We expect our results to significantly improve understanding of the
interaction between LSD gene loss and PD susceptibility, including potential dose-dependent
interactions that are not addressed in current models.

## Key facts

- **NIH application ID:** 10326794
- **Project number:** 5F31NS115364-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Meigen Yu
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,636
- **Award type:** 5
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326794

## Citation

> US National Institutes of Health, RePORTER application 10326794, INTERACTIONS BETWEEN LYSOSOMAL STORAGE DISORDER GENES, SPHINGOLIPID HOMEOSTASIS, AND ALPHA-SYNUCLEIN MECHANISMS IN PARKINSON'S DISEASE (5F31NS115364-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10326794. Licensed CC0.

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