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

帕金森病中溶酶体储存障碍基因、鞘脂稳态和 α-突触核蛋白机制之间的相互作用

• 批准号: 10326794
• 负责人: Meigen Yu
• 金额: $ 3.96万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326794
• 关键词: Address; Aging; Alleles; Animals; Autophagocytosis; Biological Assay; Biological Markers; Brain; Brain Diseases; CTSD gene; Candidate Disease Gene; Ceramides; Data; Development; Disease; Disease susceptibility; Dose; Drosophila genus; Enhancers; Exclusion; Experimental Models; Experimental Parkinsonism; Future; Gaucher Disease; Genes; Genetic; Heritability; Histology; Homeostasis; Homo; Human; Human Genetics; Impairment; Investigation; Laboratories; Lewy Bodies; Link; LysoTracker; Lysosomal Storage Diseases; Mass Spectrum Analysis; Mediating; Metabolism; Modeling; NPC1 gene; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Pathologic; Pathway interactions; Patients; Penetrance; Proteins; Publishing; RNA Interference; Risk; Risk Factors; Role; Sphingolipids; Stains; Stress; Structure; Testing; Toxic effect; Transgenic Model; Transgenic Organisms; Variant; Western Blotting; Work; alpha synuclein; base; biomarker discovery; career; combinatorial; disorder risk; exome; experimental study; fly; gene function; genetic variant; glucosylceramidase; improved; knock-down; lipidomics; loss of function; metabolic profile; mutant; neurotoxicity; pre-clinical; progressive neurodegeneration; protein aggregation; protein degradation; skills; stressor; translational neuroscience

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.

项目摘要 帕金森氏病（PD）是一种无法治愈的神经退行性疾病，有强烈的证据表明 遗传力。葡萄糖酶酶（GBA）中变体的杂合存在增加PD 与非携带者相比，风险增加了五倍。但是，部分损失的机制 葡萄糖脑苷酶功能有助于PD易感性。完全损失 葡萄糖脑苷酶功能导致高彻氏病，这是54种稀有常染色体隐性 或称为溶酶体储存障碍（LSD）的X连锁疾病。最近从我的 实验室表明，LSD基因变异的Burnen与PD风险显着相关，甚至 排除GBA，表明除GBA以外的LSD基因可能有助于 PD发病机理的发作。有趣的是，几个隐含基因在共享中起作用 鞘脂代谢途径，类似于GBA。对于我的项目，我将使用果蝇 研究以下假设，即LSD基因功能的部分或单倍损失会破坏 鞘脂代谢，导致增强的溶酶体胁迫和增加的脆弱性 与PD相关的应激源，例如α-突触核蛋白的毒性和衰老。我的项目利用我的 初步数据，其中我筛选了300多个转基因果蝇线以识别21 LSD 敲低增强α-突触核蛋白毒性的基因。我将确认 增强以确定这些LSD基因的部分损失可能有助于PD 敏感性。我的项目还通过使用不同的不同 GBA功能突变体丧失的优势。我将分析这些突变体的剂量依赖性 使用基于质谱的脂质组学破坏鞘脂代谢， 试图与其他LSD基因进一步扰动鞘脂代谢 神经变性。我们希望我们的结果将显着提高对 LSD基因丧失与PD敏感性之间的相互作用，包括潜在的剂量依赖性 当前模型中未解决的交互。