Axonal endo-lysosome transport mechanisms that regulate APP processing

调节 APP 加工的轴突内溶酶体转运机制

• 批准号: 10219145
• 负责人: SHAWN FERGUSON
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219145
• 关键词: Abeta synthesis; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Autophagocytosis; Axon; Axonal Transport; Binding; Biogenesis; Biological; Brain Pathology; Cells; Cellular biology; Coupled; Dangerousness; Defect; Dementia; Development; Disease; Disease Progression; Dynein ATPase; Endosomes; Environment; Exhibits; Foundations; Frontotemporal Dementia; Genes; Genetic study; Hereditary Spastic Paraplegia; Homeostasis; Human; Human Genetics; Investigation; Knockout Mice; Lead; Light; Lysosomes; MAPK8 gene; Mediating; Molecular; Motor; Mus; Neurodegenerative Disorders; Neurons; Organelles; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pattern; Peptides; Phenotype; Play; Population; Process; Production; Proteins; Regulation; Research; Risk Factors; Role; Senile Plaques; Site; Swelling; Testing; Therapeutic; Transgenic Mice; amyloid precursor protein processing; base; beta-site APP cleaving enzyme 1; brain tissue; design; experimental study; gene function; genetic approach; imaging approach; in vivo; induced pluripotent stem cell; insight; mouse model; novel strategies; novel therapeutic intervention; novel therapeutics; presenilin-2; protein protein interaction; retrograde transport; scaffold; therapeutic development

Our research will take a cell biology approach to investigate mechanisms controlling axonal lysosome transport and maturation. Through these efforts we will seek to define how defects in the axonal transport and maturation of lysosomes create a sub-cellular environment that is highly conducive to the amyloidogenic processing of APP and the development of amyloid plaque pathology. These efforts are motivated by human genetics studies that have identified multiple genes encoding endo-lysosomal pathway proteins as AD risk factors as well as the well established but poorly understood local accumulation of lysosomes within swollen axons that surround amyloid plaques. Although such lysosome accumulations are widely found in human AD brain tissue and are recapitulated in transgenic mouse models that develop amyloid plaques, the contributions of these lysosomes (either protective or deleterious) on disease progression or dementia are not known. Based on our previous investigation of the amyloid plaque-associated axonal lysosome accumulations and axonal lysosome transport mechanisms, we hypothesize that defects in axonal lysosome transport and maturation create hotspots for amyloidogenic APP processing. Therefore, to investigate the contribution of defective axonal lysosome transport to APP processing and Aβ peptide production, we aim to: (1) Define mechanisms that control axonal lysosome abundance; (2) Establish the impact of axonal transport defects on amyloid precursor protein processing, Aβ production and the development of amyloid plaque pathology. Central to these proposed studies is our recent discovery of a robust defect in the coordinated process of axonal lysosome transport and maturation in neurons from JNK-interacting protein 3 (JIP3) knockout mice. Through our proposed efforts to dissect the mechanisms whereby JIP3 regulates axonal lysosomes and their ability to serve as sites of APP processing, we will gain new insight into possible pathogenic roles played by these organelles in Alzheimer's disease. Focusing on this specific subcellular environment that is so supportive of the amyloidgenic processing of APP has the potential to identify new strategies to specifically suppress the most dangerous sub-cellular sites for APP processing while sparing potentially beneficial functions of genes such as APP, BACE1 and PSENs. This research could thereby lead to novel therapeutic opportunities focused on manipulating axon lysosome biogenesis and/or transport to limit both Aβ production and neuronal pathology. New insights into the cell biology of neuronal lysosomes revealed by the proposed studies are expected to have additional broad relevance to other neurodegenerative diseases with lysosomal contributions to their pathology such as Parkinson's disease, frontotemporal dementia and hereditary spastic paraplegia.

我们的研究将采用细胞生物学的方法来研究轴突溶酶体转运的控制机制 和成熟。通过这些努力，我们将试图确定轴突运输缺陷和 溶酶体的成熟创造了一个亚细胞环境， APP的加工和淀粉样斑块病理学的发展。这些努力的动机是人类 遗传学研究已经确定了多种编码内溶酶体途径蛋白的基因作为AD风险 这些因素以及已经确立但知之甚少的局部溶酶体积累， 淀粉样斑块周围的轴突虽然这种溶酶体积累在人类AD中广泛存在， 脑组织，并在转基因小鼠模型中重演，发展淀粉样蛋白斑块， 这些溶酶体（保护性或有害的）对疾病进展或痴呆的影响尚不清楚。 基于我们之前对淀粉样斑块相关轴突溶酶体积聚的研究 和轴突溶酶体转运机制，我们假设轴突溶酶体缺陷， 运输和成熟为淀粉样蛋白生成APP加工产生热点。因此，为了调查 有缺陷的轴突溶酶体转运对APP加工和Aβ肽产生的贡献，我们的目标是 目的是：（1）确定控制轴突溶酶体丰度的机制;（2）确定轴突溶酶体的影响。 转运缺陷对淀粉样前体蛋白加工、Aβ生成和淀粉样蛋白形成的影响 斑块病理学这些研究的核心是我们最近发现了一个强大的缺陷， JNK相互作用蛋白3介导的轴突溶酶体转运和神经元成熟的协调过程 （JIP 3）敲除小鼠。通过我们提出的努力，剖析JIP 3调节轴突的机制， 溶酶体及其作为APP加工位点的能力，我们将获得新的见解， 这些细胞器在阿尔茨海默病中所起的致病作用。专注于这种特定的亚细胞 支持APP淀粉样蛋白加工的环境具有识别新的 策略，专门抑制APP处理的最危险的亚细胞位点，同时保留 潜在的有益功能的基因，如APP，BACE 1和PSENs。这项研究可能会导致 新的治疗机会集中在操纵轴突溶酶体生物发生和/或运输以限制 Aβ生成和神经病理学。对神经元溶酶体细胞生物学的新见解揭示 通过拟议的研究，预计对其他神经退行性疾病具有额外的广泛相关性。 与溶酶体的贡献，他们的病理，如帕金森氏病，额颞叶痴呆症， 遗传性痉挛性截瘫