Parkinson?s disease (PD) is the second most common neurodegenerative disease, and ~60,000 veterans currently receive care for PD from the VA Health Care System annually. PD is characterized by progressive motor decline and cognitive impairment. Despite significant medical burden, our understanding of the pathogenesis of PD and therapies remain limited. Mutations in the gene glucosidase, beta acid 1 (GBA1) are the strongest genetic risk factor for developing idiopathic PD, increasing risk by ~5-fold in GBA1 mutation carriers compared to controls. However, most individuals with GBA1 mutations do not develop PD, suggesting that additional genetic modifiers influence PD susceptibility. Identification of these modifiers would provide insight into the pathogenesis of PD, and reveal novel targets for disease-modifying therapies. The proposed work focuses on identifying genetic modifiers of GBA1-mediated neurodegeneration using a Drosophila GBA1 deficient model, using these modifiers to understand the pathogenic mechanisms causing PD, and determining whether modifiers identified in Drosophila translate to clinically relevant modifiers of human disease. Candidate modifiers will be identified through a genetic screen using a GBA1 deficient Drosophila model that I have developed (Aim 1). Two candidate modifiers, brainwashing (bwa) and glucosylceramide transferase 1 (GlcT-1) have already been identified in preliminary work. The function of these modifiers in ceramide metabolism suggests that decreased levels of ceramide may be responsible for GBA1-mediated neurodegeneration. I hypothesize that decreased ceramide levels impair fusion of autophagosomes to lysosomes, causing neurodegeneration. I will test this hypothesis by identifying alterations of lipid abundances in GBA1 mutant and control flies with overexpression or loss of function of bwa and GlcT-1, and examining resulting effects on autophagy flux and autophagosome morphology (Aim 2). I will also test whether increasing levels of ceramide directly through dietary supplementation can ameliorate GBA1 mutant phenotypes, including impaired autophagy. These studies will elucidate the mechanistic link between lipid metabolism and pathologic protein aggregation in GBA1-mediated pathogenesis, which has remained elusive.
In Aim 3, I will test whether bwa and GlcT-1 are also modifiers of human disease, by analyzing human homologs of these modifiers for association with rate of progression of symptoms in a longitudinal cohort of GBA1 carriers and noncarriers with PD (Aim 3). The proposed work uses several innovative approaches, including a novel invertebrate model of GBA1 deficiency manifesting phenotypes suggestive of PD, testing the role of lipid metabolism on autophagy through genetic perturbations and dietary supplementation, and attempting to translate findings from a Drosophila model to PD patients. This work will significantly advance our understanding of PD pathogenesis, and could reveal novel therapeutic targets and new lipidomic biomarkers. I plan to use the proposed methodologies in Aims 2 and 3 to investigate the mechanisms of additional modifiers identified through the proposed work. This will provide exciting avenues for new discoveries, elucidate pathogenic mechanisms responsible for PD, and form the basis for a Merit Award proposal, to be submitted during the CDA2. My interests in lipid metabolism alterations contributing to neurodegeneration, and translation of findings from a Drosophila model to a cohort of PD patients already differentiate me from my mentors, and the additional training in these areas will allow me to successfully transition to an independent researcher combining mechanistic experimental work in Drosophila with clinically relevant findings in humans.
The pathogenesis of Parkinson?s disease (PD) is poorly understood. My research seeks to understand pathogenic mechanisms in PD by exploring PD related to glucosidase, beta acid 1 (GBA1), a gene identified as the strongest known genetic risk factor for PD. However, most individuals with GBA1 deficiency do not develop PD, suggesting a critical role for genetic modifiers. I will identify modifiers of GBA1 pathogenicity using an unbiased Drosophila genetic screen based on a novel Drosophila GBA1 deficiency model. Preliminary results from this screen have identified modifiers that suggest a model where changes in ceramide cause the neurodegeneration seen in GBA1-associated PD. In addition to testing this hypothesis, I will also test whether modifiers identified by the Drosophila model translate to modification of rate of progression of motor and or cognitive symptoms in patients with PD. The potential impact of this proposal is large, as it could lead to clinically translatable findings, and novel therapeutic targets for PD, a common neurodegenerative disease.