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

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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.