Progranulin, Prosaposin and Lipid Biology in FTD

FTD 中的颗粒体蛋白前体、前塞波辛和脂质生物学

• 批准号: 10464157
• 负责人: Aimee Kao
• 金额: $ 139.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464157
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Apoptosis; Biology; CTSL gene; Caenorhabditis elegans; Cathepsin L; Cathepsins; Cell Death; Complex; Data; Dementia; Development; Disease; Disulfides; Event; Exhibits; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Genetic; Glycoproteins; Goals; Health; Homeostasis; Human; Impairment; Individual; Inflammation; Knowledge; Lead; Length; Life; Link; Lipids; Lysosomes; Mediating; Membrane; Metabolism; Mission; Modeling; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organelles; Outcome; PGRN gene; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peptides; Play; Population; Process; Production; Proteins; Public Health; Regulation; Research; Role; Saposins; Signal Transduction; Sphingolipids; Stress; System; Tissues; Translating; United States National Institutes of Health; Work; biological adaptation to stress; burden of illness; granulin; insight; lipid metabolism; loss of function mutation; new therapeutic target; pleiotropism; protein TDP-43; protein metabolism; proteostasis; targeted treatment; trafficking

PROJECT SUMMARY Loss-of-function mutations in the progranulin gene (Pgrn haploinsufficiency) cause genetic forms of FTLD with TDP-43 inclusions. The PGRN protein and its bioactive cleavage fragments, the “granulins,” directly modulate activity of the lysosomal protease cathepsin D (CTSD). PGRN traffics to the lysosome as a heterodimer with prosaposin (PSAP). PSAP regulates the levels of sphingolipids, an important class of lipids with roles in intra- cellular signaling, membrane trafficking and apoptosis. The specific effects of Pgrn haploinsufficiency on prote- ase biology, sphingolipid metabolism and how PGRN and PSAP coordinately regulate protein and lipid home- ostasis remain largely unaddressed. We aim to fill these major gaps in knowledge by delineating the complex, downstream effects of PGRN and its cleavage products on lysosomal function. Our long-term goal is to under- stand how aging and disease-associated lysosomal dysfunction promote neurodegenerative disease. In this application, our overall objective is to determine how Pgrn haploinsufficiency impacts downstream processes such as protease and sphingolipidase activity, TDP-43 and sphingolipid breakdown, and overall protein and lipid homeostasis. Our central hypothesis is that Pgrn haploinsufficiency, via modulation of CTSD activity, con- fers a “double hit” on protein and lipid metabolism, which impairs both TDP-43 and sphingolipid degradation, ultimately leading to negative downstream consequences on lysosomal function and cellular health. The ra- tionale for our work is that by understanding how PGRN, PSAP and their cleavage products regulate protein and lipid metabolism, we will gain key insights into the mechanisms of neurodegenerative disease pathophysi- ology. Thus, we propose the following specific aims: 1) Determine how PGRN and its cleavage products affect CTSD-mediated TDP-43 breakdown and protein homeostasis; 2) Understand the impact that PGRN and its cleavage products play on saposin production, sphingolipid levels and lipid homeostasis; 3) Interrogate the ef- fects of Pgrn haploinsufficiency on lysosomal protease and lipidase pathways in humanized models. Upon successful completion of the proposed research, we will have gained understanding of how PGRN impacts downstream lysosomal processes such as protease and sphingolipidase activity, TDP-43 and sphingolipid breakdown, and overall protein and lipid homeostasis. This contribution is significant because it will lead to a comprehensive understanding of the complex, age- and disease-associated events associated with Pgrn hap- loinsufficiency. This will further translate into better, more rationally targeted approaches to therapy in FTLD- Pgrn and allow better understanding of the basic biology of the lysosome, how proteases and sphingolipidases can be coordinately regulated and how dysfunctional protein and lipid metabolism contribute to FTLD patho- genesis.

项目摘要 颗粒蛋白前体基因的功能缺失突变（Pgrn单倍不足）导致FTLD的遗传形式， TDP-43夹杂物。PGRN蛋白及其生物活性切割片段，“颗粒蛋白”， 溶酶体蛋白酶组织蛋白酶D（CTSD）的活性。PGRN作为异二聚体运输到溶酶体， 鞘脂激活素原（PSAP）。PSAP调节鞘脂的水平，鞘脂是一类重要的脂质， 细胞信号传导、膜运输和凋亡。Pgrn单倍不足对蛋白质表达的特异性影响 酶生物学，鞘脂代谢以及PGRN和PSAP如何协调调节蛋白质和脂质的家园- 经济停滞基本上仍未得到解决。我们的目标是通过描绘复杂的， PGRN及其裂解产物对溶酶体功能的下游作用。我们的长期目标是-- 说明衰老和疾病相关的溶酶体功能障碍如何促进神经退行性疾病。在这 我们的总体目标是确定Pgrn单倍不足如何影响下游过程 例如蛋白酶和鞘脂酶活性、TDP-43和鞘脂分解以及总蛋白质和 脂质稳态我们的中心假设是Pgrn单倍不足，通过调节CTSD活性， 对蛋白质和脂质代谢产生“双重打击”，这会损害TDP-43和鞘脂降解， 最终导致对溶酶体功能和细胞健康的负面下游后果。那个... 通过了解PGRN、PSAP及其切割产物如何调节蛋白质， 和脂质代谢，我们将获得神经退行性疾病病理生理机制的关键见解- 学。因此，我们提出以下具体目标：1）确定PGRN及其裂解产物如何影响 CTSD介导的TDP-43分解和蛋白质稳态; 2）了解PGRN及其对细胞内环境的影响。 裂解产物对鞘脂激活蛋白的产生、鞘脂水平和脂质体内平衡起作用; 3）询问裂解产物对鞘脂激活蛋白产生的影响。 在人源化模型中Pgrn单倍不足对溶酶体蛋白酶和脂酶途径的影响。后 成功完成拟议的研究，我们将了解PGRN如何影响 下游溶酶体过程如蛋白酶和鞘脂酶活性、TDP-43和鞘脂 分解以及整体蛋白质和脂质体内平衡。这一贡献意义重大，因为它将导致 全面了解与Pgrn hap相关的复杂、年龄和疾病相关事件， 腰部功能不全这将进一步转化为更好、更合理的FTLD治疗方法- Pgrn和允许更好地理解溶酶体的基本生物学， 可以协调调节，以及功能失调的蛋白质和脂质代谢如何导致FTLD病理性 创世纪