Endosomal lysosomal function in neuronal storage disease

神经元贮积病中的内体溶酶体功能

• 批准号: 9787597
• 负责人: KOSTANTIN DOBRENIS
• 金额: $ 5.53万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9787597
• 关键词: Adaptor Signaling Protein; Address; Affect; Amino Acids; Articulation; Autophagocytosis; Autophagosome; Biogenesis; Brain; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Cellular Metabolic Process; Cessation of life; Cholesterol; Complex; Defect; Dendrites; Deterioration; Development; Disease; Elements; Event; FRAP1 gene; Family; Family Felidae; Fatty Acids; Functional disorder; G(M2) Ganglioside; Gangliosides; Gene Activation; Gene Expression Regulation; Genes; Genetic Diseases; Goals; Growth; Growth Factor; Health; Heterogeneity; Human; In Vitro; Incidence; Individual; Link; Live Birth; Lysosomal Storage Diseases; Lysosomes; Membrane; Metabolic Pathway; Mitotic; Modeling; Mus; Neurologic; Neurons; Nuclear; Nutrient; Organelles; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phosphorylation; Population; Process; Proteins; Reading; Recycling; Regulation; Research; Role; Series; Signal Transduction; Starvation; Stream; Surface; System; TFE3 gene; Thinking; Up-Regulation; Vesicle; cell growth; cytotoxicity; design; hippocampal pyramidal neuron; in vivo; insight; late endosome; neuronal metabolism; new growth; programs; sensor; sensorimotor system; therapy development; transcription factor

Lysosomal diseases represent a group of nearly 60 monogenic human disorders caused by defects in proteins involved in normal functioning of the lysosomal system. Most severely impact the brain, cause progressive neurological deterioration over years to decades, and are fatal. Pathogenic cascades caused by lysosomal dysfunction are remarkably complex and involve diverse and unusual events ranging from the blockage of autophagy to the growth of bizarre and unique (to lysosomal diseases) “ectopic” dendrites on cortical pyramidal neurons. To provide a conceptual framework for understanding this complexity we developed in 2009 the concept of a “Greater Lysosomal System” which put the lysosome at center stage in the cell's recycling process, receiving “streams” of different metabolites from both endosomal and autophagosomal pathways. We also emphasized “egress” of catabolic products from lysosomes since lack of such salvage would be anticipated to result in deficient precursors for metabolic pathways and possible up-regulation of synthesis or induction of autophagy to overcome such deficiency. Importantly, recent discoveries give credence to this concept – most notably that a master regulator of cell metabolism, the mammalian target of rapamycin (mTOR, specifically mTORC1), is anchored at the surface of lysosomes. Here, among a myriad of functions, it controls the translocation of the MITF family of transcription factors (e.g., TFEB, TFE3) which themselves regulate hundreds of genes involved in autophagy and lysosomal biogenesis. Thus much evidence now supports the idea of the lysosome as the cell's “nutrient sensor”, allowing for orchestration of cell growth programs during periods of high nutrient availability and facilitating autophagy during nutrient starvation. We believe this is the most important window yet discovered through which to investigate the basis for the complexity of pathogenic mechanisms in lysosomal diseases. A central goal of the current proposal is therefore to analyze mTOR function across a carefully selected but diverse group of lysosomal diseases and to do so in concert with our earlier and ongoing studies focused on the heterogeneity of lysosomal storage, the dysregulation of autophagy and p62 aggregation, and the unique growth of new, primary dendrites on cortical pyramidal neurons undergoing lysosomal storage of gangliosides. Thus we propose three highly interlinked specific aims: The first to further characterize lysosomal storage heterogeneity as well as p62 aggregation and its relationship to lysosomes; the second to investigate the impact of lysosomal storage on mTORC1 pathway hypo- and hyperactivation and the consequences of each; and the third to determine the association between altered mTOR activation and changes in dendritic complexity, including so-called “ectopic dendritogenesis”.

溶酶体疾病代表了一组近60种单基因性人类疾病，由缺陷引起 参与溶酶体系统正常功能的蛋白质。最严重影响大脑，原因 几十年来的渐进神经系统决定性，并且致命。致病级联 溶酶体功能障碍非常复杂，涉及各种各样的事件，从 在奇异和独特的（溶酶体疾病）上的自噬阻塞“异位”树突上 皮质锥体神经元。为了理解这种复杂性的概念框架，我们 在2009年开发了“更大的溶酶体系统”的概念，该概念使溶酶体处于中心位置 细胞的回收过程，从内体和自噬体中接收不同代谢物的“流” 途径。我们还强调了溶酶体的分解代谢产物的“出口”，因为缺乏这种打捞 预计会导致代谢途径的不足前体和可能的上调 合成或诱导自噬以克服这种缺陷。重要的是，最近发现 对这个概念的信任 - 最著名的是细胞代谢的主要调节剂，这是 雷帕霉素（MTOR，特别是MTORC1）锚定在溶酶体的表面。在这里，无数 功能，它控制着MITF转录因子家族的易位（例如TFEB，TFE3） 自己调节了数百个参与自噬和溶酶体生物发生的基因。这么多 现在的证据支持溶酶体作为细胞的“营养传感器”的想法，允许细胞编排 在养分较高的可用性期间的增长计划和营养饥饿期间的自噬。 我们认为这是迄今为止发现的最重要的窗口，可以调查 溶酶体疾病中致病机制的复杂性。当前提议的一个核心目标是 因此，分析了经过精心选择但多样化的溶酶体疾病的MTOR功能，并 与我们的早期和正在进行的研究一致，重点是溶酶体存储的异质性， 自噬和p62聚集的失调，以及新的主要树突在皮质上的独特生长 锥体神经元的锥体神经元。我们提出了三个高度互联的 具体目的：第一个进一步表征溶酶体存储异质性以及p62聚合和 它与溶酶体的关系；第二个研究溶酶体存储对MTORC1途径的影响 低激活和每个人的后果；第三个确定关联 MTOR激活改变和树突复杂性的变化，包括所谓的“异位树突生成”。