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

项目摘要 致病性蛋白质聚集体是许多神经系统疾病的标志性神经病理学发现。 神经退行性疾病迄今为止，大多数研究都集中在这些致病性 形成聚集体。然而，人们对聚集体形成的机制知之甚少。 在细胞间传播，这是神经退行性疾病进展的标志。帕金森 疾病（PD）是第二常见的神经退行性疾病。的基因突变 葡糖苷酶β酸1（GBA），其编码产生神经酰胺的溶酶体酶，是神经酰胺的主要来源。 PD的最强遗传风险因素。最近，GBA突变也被发现与 加速认知和运动症状进展，表明GBA突变影响 蛋白质聚集体在大脑中的扩散。PD和其他神经退行性疾病的最新研究 疾病表明，脂质代谢，特别是神经酰胺的失调， 在发病机制中的重要作用。我们最近的工作揭示了GBA在调节 细胞外囊泡（EV）形成和货物。我假设GBA缺乏会更快地 通过EV的失调，蛋白质聚集体从细胞到细胞的繁殖。探讨 GBA突变影响蛋白质聚集体繁殖的机制 我将使用果蝇、小鼠和人类的神经细胞培养 GBA缺乏模型。我推测由于GBA缺乏导致的神经酰胺水平降低 导致EV的失调，其促进蛋白质聚集体从细胞到细胞的转移 并导致神经退化的更快发展。了解潜在的机制 朊病毒样蛋白聚集体的繁殖有可能揭示新的治疗方法， 这些靶点可以减缓或阻止PD和其他神经退行性疾病， 传播致病蛋白质聚集。

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.