Understanding Susceptibility to Parkinson's Disease due to GBA1 Mutations

了解 GBA1 突变对帕金森病的易感性

• 批准号: 10643798
• 负责人: Marie Ynez Davis
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10643798
• 关键词: Acids; Affect; Age; Age-Years; Alpha-glucosidase; Area; Autophagocytosis; Autophagolysosome; Autophagosome; Award; Biological Assay; Biological Markers; Caring; Ceramides; Cognitive; Data; Defect; Dietary Supplementation; Disease; Disease Progression; Disease model; Disease susceptibility; Drosophila genus; Enzymes; Evaluation; Fat Body; Gene Frequency; Genes; Genetic; Genetic Screening; Glucose; Glucosylceramides; Healthcare Systems; Human; Idiopathic Parkinson Disease; Impaired cognition; Impairment; Individual; Invertebrates; Lead; Learning; Libraries; Link; Lipids; Longevity; Longitudinal cohort; Lysosomes; Measures; Mediating; Medical; Mentors; Metabolism; Methodology; Minor; Modeling; Modification; Morphology; Motor; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Mutation; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Organelles; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Patients; Performance; Persons; Phenotype; Play; Predisposition; Research; Research Personnel; Risk; Role; Screening Result; Suggestion; Symptoms; Techniques; Testing; Time; Training; Transferase; Translating; Translations; Variant; Veterans; Western Blotting; Work; aging population; base; career; clinical heterogeneity; clinically relevant; clinically translatable; cognitive testing; cohort; fly; genetic risk factor; genomic locus; glucosidase; human disease; improved; innovation; insight; interest; lipid metabolism; lipidomics; locomotor deficit; loss of function; motor symptom; mutant; mutation carrier; new therapeutic target; next generation sequencing; novel; overexpression; protein aggregation; protein biomarkers; screening; sex; thought control

PROJECT SUMMARY 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.

项目总结

项目成果

Glucocerebrosidase deficiency promotes protein aggregation through dysregulation of extracellular vesicles.

• DOI: 10.1371/journal.pgen.1007694
• 发表时间: 2018-09
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Thomas RE;Vincow ES;Merrihew GE;MacCoss MJ;Davis MY;Pallanck LJ
• 通讯作者: Pallanck LJ

Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles.

• DOI: 10.1371/journal.pgen.1008859
• 发表时间: 2021-03
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Jewett KA;Thomas RE;Phan CQ;Lin B;Milstein G;Yu S;Bettcher LF;Neto FC;Djukovic D;Raftery D;Pallanck LJ;Davis MY
• 通讯作者: Davis MY