Investigating the role of lipid metabolism in protein aggregation and neurodegenerative disease progression

研究脂质代谢在蛋白质聚集和神经退行性疾病进展中的作用

基本信息

批准号：
10402005
负责人：
Marie Ynez Davis
金额：
$ 3.98万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-06 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402005
关键词：
Acids Affect Alzheimer&apos s Disease Biogenesis Brain Cell Culture Techniques Cells Ceramides Clinical Dementia with Lewy Bodies Disease Progression Drosophila genus Enzymes Gaucher Disease Genes Genetic Glucose Glucosylceramides Human Impaired cognition Kinetics Lead Lewy body pathology Link Lipids Lysosomal Storage Diseases Mediating Membrane Metabolism Modeling Molecular Chaperones Morphology Motor Mus Mutation Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neuromuscular Junction Neurons Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathogenicity Patients Phenotype Process Production Proteins Proteomics Reporter Research Risk Role System Testing Tissues Work alpha synuclein experimental study extracellular vesicles fly genetic risk factor glucosidase glucosylceramidase in vivo induced pluripotent stem cell lipid metabolism lipidomics motor symptom mouse model new therapeutic target novel prion-like protein aggregation proteostasis stem cell model tau-1 trafficking

项目摘要

PROJECT SUMMARY Pathogenic protein aggregates are a hallmark neuropathologic finding in many neurodegenerative diseases. Most research has thus far focused on how these pathogenic aggregates are formed. However, little is known about the mechanism by which aggregates spread from cell to cell, a hallmark of neurodegenerative disease progression. Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in the gene glucosidase beta acid 1 (GBA), which encodes a lysosomal enzyme producing ceramide, are the strongest genetic risk factor for PD. Recently, GBA mutations were also found to associate with accelerated cognitive and motor symptom progression, suggesting that GBA mutations influence the spread of protein aggregates within the brain. Recent work in PD and other neurodegenerative diseases suggest that dysregulation of lipid metabolism, and in particular ceramide, also has an important role in pathogenesis. Our recent work revealed a novel function for GBA in regulating extracellular vesicle (EVs) formation and cargo. I hypothesize that GBA deficiency mediates faster propagation of protein aggregates from cell to cell through dysregulation of EVs. To investigate the mechanisms by which GBA mutations influence the propagation of protein aggregates between tissues and between cells, I will use Drosophila, mouse and human neuronal cell culture models of GBA deficiency. I hypothesize that decreased ceramide levels due to GBA deficiency lead to dysregulation of EVs, which promotes the transfer of protein aggregates from cell to cell and leads to faster progression of neurodegeneration. Understanding the mechanisms underlying the prion-like propagation of protein aggregates has the potential to reveal novel therapeutic targets that could slow or halt PD and other neurodegenerative diseases characterized by the spread of pathogenic protein aggregation.

项目摘要致病蛋白聚集体是许多人的标志性神经病理发现神经退行性疾病。迄今为止，大多数研究都集中在这些病原体上聚集体形成。但是，关于聚集的机制知之甚少从细胞到细胞，这是神经退行性疾病进展的标志。帕金森氏症疾病（PD）是第二个最常见的神经退行性疾病。基因突变葡萄糖酶β酸1（GBA）编码产生神经酰胺的溶酶体酶是 PD的最强遗传危险因素。最近，还发现GBA突变与加速认知和运动症状的进展，表明GBA突变会影响蛋白质聚集体在大脑内的扩散。 PD和其他神经退行性的最新工作疾病表明脂质代谢的失调，尤其是神经酰胺，也有一个在发病机理中的重要作用。我们最近的工作揭示了GBA在调节中的新功能细胞外囊泡（EV）形成和货物。我假设GBA缺乏症可以更快地介导通过EV的失调，蛋白质聚集体从细胞到细胞的传播。调查 GBA突变影响蛋白质聚集体的传播的机制在组织和细胞之间，我将使用果蝇，小鼠和人类神经元细胞培养 GBA缺乏型的模型。我假设由于GBA缺乏症而导致的神经酰胺水平降低导致EV的失调，这促进了蛋白质聚集体从细胞到细胞的转移并导致神经退行性的进展更快。了解基本机制蛋白质聚集体的prion样传播具有揭示新型治疗的潜力可能减慢或停止PD和其他神经退行性疾病的靶标的靶标的致病蛋白聚集的扩散。