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

项目总结 致病蛋白聚集体是许多患者的标志性神经病理发现 神经退行性疾病。到目前为止，大多数研究都集中在这些致病因素是如何 聚集体就形成了。然而，人们对聚合的机制知之甚少。 从一个细胞传播到另一个细胞，这是神经退行性疾病进展的标志。帕金森氏症 疾病(PD)是第二常见的神经退行性疾病。该基因的突变 葡萄糖苷酶-β-酸1(GBA)编码一种产生神经酰胺的溶酶体酶，是 帕金森病最强的遗传危险因素。最近，GBA突变也被发现与 认知和运动症状加速进展，表明GBA突变影响 蛋白质聚集体在大脑中的扩散。帕金森病和其他神经退行性疾病的最新研究 疾病表明，脂代谢失调，特别是神经酰胺，也有 在发病机制中起重要作用。我们最近的工作揭示了GBA在调节中的一个新功能 胞外小泡(EVS)的形成和运输。我假设GBA缺乏能更快地调节 通过EVS的失调将蛋白质聚集体从细胞传播到细胞。去调查 GBA突变影响蛋白质聚集体繁殖的机制 在组织之间和细胞之间，我将使用果蝇、小鼠和人类神经细胞培养 GBA缺乏症模型。我推测由于GBA缺乏导致神经酰胺水平下降 导致EVS的失调，从而促进蛋白质聚集体在细胞之间的转移 并导致更快的神经退化进程。了解潜在的机制 蛋白质聚合体的类病毒繁殖有可能揭示新的治疗方法。 可以延缓或阻止帕金森病和其他神经退行性疾病的靶点 传播的致病蛋白聚集。

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.