Endosomal lysosomal function in neuronal storage disease

神经元贮积病中的内体溶酶体功能

基本信息

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
项目类别：
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

项目摘要

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”.

溶酶体疾病代表一组近 60 种单基因人类疾病，由溶酶体缺陷引起参与溶酶体系统正常功能的蛋白质对大脑的影响最严重。数年至数十年进行性神经功能恶化，并导致致命的致病级联反应。溶酶体功能障碍非常复杂，涉及多种不同寻常的事件，从阻止自噬导致奇怪且独特的（溶酶体疾病）“异位”树突的生长为了提供理解这种复杂性的概念框架，我们 2009年提出了“大溶酶体系统”的概念，将溶酶体置于研究的中心位置。细胞的回收过程，从内体和自噬体接收不同代谢物的“流” 我们还强调了分解代谢产物从溶酶体的“排出”，因为缺乏这种补救措施。预计会导致代谢途径的前体缺陷和可能的上调重要的是，最近的发现给出了自噬的合成或诱导来克服这种缺陷。这一概念的可信度——最值得注意的是，细胞代谢的主要调节者，哺乳动物的目标雷帕霉素（mTOR，特别是 mTORC1）被锚定在溶酶体的表面。它控制 MITF 转录因子家族（例如 TFEB、TFE3）的易位，它们本身调节数百个参与自噬和溶酶体生物发生的基因。现在的证据支持溶酶体作为细胞的“营养传感器”的想法，允许细胞的协调在营养丰富期间进行生长计划并在营养匮乏期间促进自噬。我们相信这是迄今为止发现的最重要的窗口，可以通过它来研究当前提案的中心目标是溶酶体疾病致病机制的复杂性。因此，要分析一组精心挑选但不同的溶酶体疾病中的 mTOR 功能，并这样做与我们早期和正在进行的研究一致，重点是溶酶体储存的异质性，自噬和 p62 聚集的失调，以及皮质上新的初级树突的独特生长锥体神经元经历神经节苷脂的溶酶体储存，因此我们提出了三种高度互连的神经节。具体目标：第一个进一步表征溶酶体储存异质性以及 p62 聚集和其与溶酶体的关系；第二个研究溶酶体储存对 mTORC1 通路的影响激活不足和过度激活以及各自的后果；第三，确定之间的关联 mTOR 激活的改变和树突复杂性的变化，包括所谓的“异位树突发生”。