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

基本信息

批准号：
10112970
负责人：
THOMAS L KUKAR
金额：
$ 38.55万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10112970
关键词：
Age Alzheimer&apos s Disease Alzheimer&apos 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 Induced pluripotent stem cell derived neurons 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

项目摘要

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.

项目概要额颞叶变性 (FTD) 和阿尔茨海默病 (AD) 是两个最常见的原因痴呆症具有重叠的病理特征，是巨大的健康负担，并且是无法治愈的。阐明颗粒体蛋白前体 (PGRN) 及其成熟产物颗粒体蛋白的损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是一种由 7.5 串联组成的分泌蛋白。通过不明确的遗传途径裂解成 6kDa 颗粒蛋白 (GRN) 的结构域。颗粒体蛋白前体基因 (Grn) 的变异和功能丧失突变，减少颗粒体蛋白前体的产生 (PGRN) 蛋白分别增加 AD 风险和导致 FTD。 PGRN/颗粒蛋白水平降低会导致溶酶体功能障碍，从而导致神经炎症和根据我们发表的工作和新数据，我们建议通过未知机制进行退化。我们发现颗粒蛋白是 PGRN 的功能单位，是在内溶酶体途径中产生的。 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蛋白。在 iPSC 衍生的神经元和 FTD-GRN 携带者的脑组织中，PGRN 和颗粒蛋白同样减少。此外，FTD 风险因子 TMEM106B 的表达会减少颗粒蛋白，最后，细胞外颗粒蛋白也会减少。拯救 Grn KO 小鼠成纤维细胞中的溶酶体缺陷，提供强有力的证据表明颗粒蛋白促进我们的研究结果符合溶酶体自噬功能障碍是一个关键因素的更广泛的叙述。 FTD 和 AD 的致病机制我们的初步数据使我们提出 PGRN 的假设。转运至溶酶体并加工成成熟的功能性颗粒蛋白，介导溶酶体成功完成以下具体目标将促进体内平衡和神经保护。神经退行性疾病领域通过提供基于机制的原理来测试颗粒蛋白作为一种新疗法 FTD 和 AD 将 1) 描述将 PGRN 运输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) 确定颗粒蛋白的体内作用 PGRN 和颗粒蛋白在溶酶体功能障碍和神经变性中的作用完成拟议的研究。使我们能够批判性地评估范式颗粒转移假设，即ins是溶酶体的、功能性的和在此过程中，我们将揭示为什么 PGRN 水平降低会导致 FTD、AD 或 NCL 以及治疗 PGRN 减少引起的疾病的新方法。