Molecular mechanisms of Progranulin in Neurodegeneration

颗粒体蛋白前体在神经退行性变中的分子机制

• 批准号: 9886298
• 负责人: THOMAS L KUKAR
• 金额: $ 38.59万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886298
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease risk; Autophagocytosis; Behavior; Brain; Carrier Proteins; Cathepsin L; Cathepsins; Cations; Cells; Cleaved cell; Clinical; Data; Defect; Dementia; Development; Disease; Enzyme Activation; Enzymes; Exhibits; Fibroblasts; Foundations; Frontotemporal Dementia; Functional disorder; Genes; Glycoproteins; Health; Homeostasis; Human; IGF2R gene; In Vitro; Inflammation; Knockout Mice; Knowledge; Lead; Link; Lysosomal Storage Diseases; Lysosomes; Mannose; Maps; Mediating; Messenger RNA; Molecular; Monoclonal Antibodies; Mus; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Ceroid-Lipofuscinosis; Neurons; PGRN gene; Pathogenicity; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Plasma; Process; Production; Proteins; Publishing; Recombinant adeno-associated virus (rAAV); Risk; Risk Factors; Role; Saposins; Site; Structure; Testing; Tissues; Variant; Work; base; brain tissue; extracellular; frontotemporal degeneration; genetic risk factor; genetic variant; granulin; in vitro activity; in vivo; induced pluripotent stem cell; knock-down; loss of function mutation; lysosomal proteins; mutation carrier; neuroinflammation; neuroprotection; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; receptor; risk variant; sortilin; trafficking

Project Summary Frontotemporal degeneration (FTD) and Alzheimer’s disease (AD) are two of the most common causes of dementia, share overlapping pathologies, are huge health burdens, and are incurable. This proposal focuses on elucidating how loss of progranulin (PGRN), and its mature products the granulins, drive neurodegeneration and lysosomal dysfunction associated with FTD and AD. PGRN is a secreted protein composed of 7.5 tandem domains that are cleaved into 6kDa granulin proteins (GRNs), through a poorly defined pathway. Genetic variants and loss-of-function mutations in the progranulin gene (Grn), reduce the production of the progranulin (PGRN) protein and increase the risk of AD and cause FTD, respectively. Converging evidence suggest that decreased levels of PGRN/granulins induce lysosomal dysfunction leading to neuroinflammation and degeneration through an unknown mechanism. Based on our published work and new data, we propose that granulins are the functional unit of PGRN and are produced in the endo-lysosomal pathway. We find PGRN is trafficked to the lysosome and processed into stable granulins in multiple tissues and cells. Clinically, PGRN and granulins are equally decreased in iPSC-derived neurons and brain tissue from FTD-GRN carriers. Further, expression of the FTD-risk-factor TMEM106B reduces granulins. Finally, extracellular granulin can rescue lysosomal defects in Grn KO mouse fibroblasts, providing strong evidence that granulins facilitate lysosome function. Our findings fit into the larger narrative that lysosome-autophagy dysfunction is a critical pathogenic mechanism in FTD and AD. Our preliminary data lead us to propose the hypothesis that PGRN is trafficked to the lysosome and processed into mature, functional granulins that mediate lysosomal homeostasis and neuroprotection. Successful completion of the following specific aims will advance the neurodegeneration field by providing mechanism-based rationale for testing granulins as a novel therapy for FTD and AD. We will 1) delineate the molecular pathways that traffic PGRN to the lysosome, 2) determine the molecular mechanisms of granulin production and function in the lysosome, and 3) determine the in vivo role of PGRN and granulins in lysosome dysfunction and neurodegeneration. Completion of the proposed studies will enable us to critically evaluate the paradigm-shifting hypothesis that granulins are lysosomal, functional, and neuroprotective. In doing so, we will uncover why decreased levels of PGRN lead to FTD, AD, or NCL and a new approach to treat diseases caused by decreased PGRN.

项目摘要 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，并且是无法治愈的。这项提案将重点放在 前颗粒蛋白(PGRN)及其成熟产物颗粒丢失如何导致神经退行性变 与FTD和AD相关的溶酶体功能障碍。PGRN是一种由7.5串联组成的分泌型蛋白质 被切割成6 kDa颗粒蛋白(GRN)的结构域，通过一条不明确的途径。遗传 原颗粒蛋白基因(Grn)的变异和功能丧失突变会减少原颗粒蛋白的产生 (PGRN)蛋白和增加AD和引起FTD的风险。越来越多的证据表明 PGRN/颗粒蛋白水平降低导致溶酶体功能障碍，导致神经炎症和 通过一种未知的机制退化。根据我们已发表的工作和新的数据，我们建议 颗粒蛋白是PGRN的功能单位，通过内切溶酶体途径产生。我们发现 PGRN被运输到溶酶体，并在多种组织和细胞中加工成稳定的颗粒。在临床上， 在FTD-GRN携带者的IPSC来源的神经元和脑组织中，PGRN和颗粒素同样减少。 此外，FTD风险因子TMEM106B的表达减少了颗粒。最后，细胞外颗粒可以 挽救Grn KO小鼠成纤维细胞的溶酶体缺陷，提供强有力的证据表明颗粒促进 溶酶体功能。我们的发现符合溶酶体-自噬功能障碍是一种关键的更大的叙述 FTD和AD的致病机制。我们的初步数据使我们提出了这样的假设：PGRN是 运输到溶酶体，加工成成熟的、有功能的颗粒，介导溶酶体 动态平衡和神经保护。成功完成以下具体目标将推动 神经退行性变领域通过提供基于机制的理论来测试颗粒作为一种新的治疗方法 FTD和AD。我们将1)描绘运输PGRN到溶酶体的分子途径，2)确定 溶酶体中颗粒蛋白产生和功能的分子机制，以及3)决定颗粒蛋白在体内的作用 前列环素和颗粒蛋白与溶酶体功能障碍和神经退行性变建议的研究完成后， 使我们能够批判性地评估颗粒蛋白是溶酶体、功能性和 具有神经保护作用。在此过程中，我们将揭示为什么PGRN水平降低会导致FTD、AD或NCL以及 治疗前列腺素RN减少引起的疾病的新途径。