Resolving the function of progranulin in lysosomal lipid metabolism and the etiology of Alzheimer's disease and frontotemporal dementia

解析颗粒体蛋白前体在溶酶体脂质代谢中的功能及阿尔茨海默病和额颞叶痴呆的病因

• 批准号: 10526035
• 负责人: THOMAS L KUKAR
• 金额: $ 209.81万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526035
• 关键词: Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Binding; Brain; Brain region; C9ORF72; Catabolism; Cells; Chemicals; Crosslinker; Data; Data Analyses; Data Set; Defect; Dementia; Disease; Environment; Etiology; Evaluation; Frontotemporal Dementia; Functional disorder; Genetic; Glycoproteins; Glycosphingolipids; Government; Health; Homeostasis; Human; Hydrolase; Immunoprecipitation; Impairment; Induced pluripotent stem cell derived neurons; Lead; Link; Lipids; Lysosomes; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Microglia; Molecular; Monoglycerides; Mus; Mutation; Nerve Degeneration; Neurons; PGRN gene; Pathogenicity; Pathology; Pathway interactions; Persons; Phospholipids; Plasma; Process; Production; Proteins; Proteome; Proteomics; Publishing; Reagent; Recombinants; Resources; Risk; Sphingomyelinase; Sphingomyelins; System; Systems Biology; Testing; Tissues; Work; base; brain health; frontotemporal degeneration; genetic variant; granulin; induced pluripotent stem cell; insight; lipid metabolism; lipidome; loss of function mutation; metabolome; mutation carrier; new therapeutic target; novel; prevent

Frontotemporal degeneration (FTD) and Alzheimer's disease (AD) are two of the most common causes of dementia, share overlapping pathologies, are huge health burdens, yet are incurable. This proposal focuses on elucidating how loss of progranulin (PGRN) causes lysosome dysfunction and lipid dysregulation associated with FTD and AD. PGRN is a secreted protein composed of 7.5 tandem domains called granulins. Genetic variants and loss-of-function mutations in the progranulin gene (GRN), reduce PGRN and increase the risk of AD and cause FTD, respectively. Despite its importance in brain health, the exact function of PGRN and granulins are unknown. We have discovered that PGRN is cleaved into 6 kDa granulin proteins in the lysosome. Work from our lab and others support the idea that PGRN serves as a precursor to lysosomal granulins, which mediate lysosome homeostasis and loss of granulins causes impaired lysosome function. However, the function of granulins in the lysosome remains elusive. Based on our published work and new data, we propose that loss of granulins impair lysosomal lipid metabolism, which is the primary defect that ultimately leads to neurodegeneration. Integrated analysis of the Grn−/− mouse metabolome and lipidome revealed early accumulation of glycosphingolipids, phospholipids, and monoglycerides. Systems biology analysis of these data identify dysregulated lysosomal lipid flux as a primary defect in Grn−/− tissue. Further, we pinpoint decreased activity of a novel lysosomal hydrolase as a key factor. Based on these data, we hypothesize that granulins bind and modulate the activity of lysosomal lipid hydrolases to prevent lipid accumulation and neurodegeneration. In this project we will 1) determine the global and lysosome-specific molecular defects caused by PGRN deficiency in human induced pluripotent stem cell (iPSC)-derived neurons and microglia, 2) test the hypothesis that granulins modulate activity of lipid hydrolases in the lysosomal lumen, and 3) define how PGRN deficiency alters the metabolome and lipidome in mice and humans. Completion of these studies will provide novel systems-level insight into the function of granulins in the lysosome. The reagents and data we generate will be widely shared to advance our field's understanding of PGRN function. Our team is ideally suited to complete the proposed studies, which critically evaluate the novel hypothesis that granulins facilitate metabolism of distinct lipids in the lysosome through activation of novel lipid hydrolases to prevent lipid accumulation and neurodegeneration. In doing so, we will uncover why decreased levels of PGRN and granulins cause FTD, AD, and reveal new targets to treat diseases caused by PGRN deficiency.

额颞退行性变(FTD)和阿尔茨海默病(AD)是最常见的两种原因 痴呆症的共同病理重叠是巨大的健康负担，但却是无法治愈的。这项提案将重点放在 原颗粒丢失(PGRN)导致溶酶体功能障碍和血脂紊乱的机制探讨 与FTD和AD相关。PGRN是一种由7.5个串联结构域组成的分泌型蛋白质，称为颗粒蛋白。 原颗粒蛋白基因(GRN)的遗传变异和功能丧失突变会减少PGRN并增加 AD的风险和引起FTD的风险。尽管PGRN对大脑健康很重要，但它的确切功能 颗粒蛋白是未知的。我们发现PGRN在细胞内被切割成6 kDa的颗粒蛋白。 溶酶体。我们实验室和其他实验室的工作支持PGRN是溶酶体的前体的观点 介导溶酶体动态平衡和颗粒丢失的颗粒素会导致溶酶体功能受损。 然而，溶酶体中颗粒的功能仍然难以捉摸。基于我们已发表的工作和新的 数据，我们认为颗粒丢失损害溶酶体脂代谢，这是主要的缺陷。 这最终会导致神经退化。GRN-−/−小鼠代谢组和脂质体的整合分析 揭示了糖鞘糖脂、磷脂和单甘酯的早期积累。系统生物学 对这些数据的分析表明，溶酶体脂流量失调是GRN−/−组织的主要缺陷。此外，我们 Pinpoint降低一种新的溶酶体水解酶的活性是一个关键因素。根据这些数据，我们 假设颗粒结合并调节溶酶体脂水解酶的活性以预防脂质 积聚和神经变性。在这个项目中，我们将1)确定全局和特定于溶酶体的 前列腺素RN缺乏引起的人诱导多能干细胞来源神经元的分子缺陷 和小胶质细胞，2)检验颗粒蛋白调节溶酶体腔内脂水解酶活性的假设， 以及3)确定PGRN缺乏如何改变小鼠和人类的代谢体和脂体。完成 这些研究将为溶酶体中颗粒蛋白的功能提供新的系统水平的洞察。这个 我们产生的试剂和数据将被广泛分享，以促进我们行业对PGRN功能的理解。 我们的团队非常适合完成拟议的研究，这些研究对新的假设进行了批判性的评估 颗粒通过激活新的脂水解酶促进溶酶体中不同脂类的新陈代谢 防止脂质堆积和神经退行性变。通过这样做，我们将揭示为什么PGRN水平下降 颗粒导致FTD、AD，为治疗PGRN缺乏引起的疾病提供了新的靶点。