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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：
10534166
负责人：
Marie Ynez Davis
金额：
$ 41.67万
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：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10534166
关键词：
Acceleration Acids Affect Alleles Alzheimer&apos s Disease Biogenesis Brain Cell Aggregation Cell Culture Techniques Cell secretion Cells Ceramides Clinical Dementia with Lewy Bodies Disease Progression Drosophila genus Enzymes Gaucher Disease Genes Genetic Glucose Glucosylceramides Heterozygote 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 Pathogenesis Pathogenicity Patients Phenotype Process Production Proteins Proteomics Reporter Research Risk Role Stereotyping 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 neuropathology new therapeutic target novel prion-like protein aggregation proteostasis stem cell model synaptotagmin 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.

项目总结