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：
7675820
负责人：
Steven Upshaw Walkley
金额：
$ 41.5万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7675820
关键词：
AMPA Receptors Address Affect Age Alzheimer&apos s Disease Area Autophagocytosis Behavioral Brain Cause of Death Cells Cerebellum Childhood Complex Connective Tissue Cystic Fibrosis Defect Dementia Dendrites Development Disease Disease model Endocytosis Endosomes Event Exhibits Family Family health status Functional disorder Gangliosides Gangliosidosis GM1 Gene Proteins Glutamate Receptor Glutamates Glycosphingolipids Goals Grant Grant Review Health Healthcare Systems Heart Hereditary Disease Immune system Impairment In Vitro Incidence Individual Inherited Life Link Live Birth Liver Lysosomes Mediating Mental Retardation Metabolic Molecular Molecular Chaperones Motor Mus Nerve Degeneration Neuroaxonal Dystrophies Neurodegenerative Disorders Neurologic Neuronal Ceroid-Lipofuscinosis Neurons Organ Organelles Pathogenesis Pathway interactions Play Process Production Proteins Psychotic Disorders Published Comment Purkinje Cells Recycling Regulation Role Seizures Sensory Signal Transduction Site Skeletal Muscle Societies Starvation Stream Stress Supraoptic Vertical Ophthalmoplegia Symptoms Synapses System Testing Time Tissues Ubiquitin Up-Regulation Viscera bone effective therapy in vivo infancy insight mouse model protein aggregation receptor research study synaptogenesis therapy development

项目摘要

Lysosomal disease represents a complex family of nearly 60 disorders linked by inherited defects in specific proteins critical for lysosomal function. At least two-thirds have significant impact on brain function, causing mental retardation, dementia, severe motor and sensory impairments, psychosis and behavioral changes, and seizures. Most lysosomal diseases have onset in infancy or childhood and dramatically compromise and shorten the lives of affected individuals. Few effective treatments, other than symptomatic, are available. The complex spectrum of neurological symptoms exhibited by individuals with lysosomal disease is reflected in a similar diversity of underlying molecular and cellular abnormalities. In addition to lysosomal storage, these include extopic dendritogenesis and altered synapse formation, axonal spheroid formation and selective neuronal degeneration. It is increasingly recognized that lysosomal diseases also exhibit alterations in autophagy as well as abnormal protein aggregation suggesting involvement of chaperone-mediated autophagy (CMA) and the ubiquitin proteosomal system (UPS). Such findings point to the presence of pathogenic cascades in lysosomal disease that resemble those in commoner forms of neurodegeneration, including Alzheimer’s and Parkingson’s diseases. Importantly, new evidence also indicates that lysosomal diseases aren’t simply states of overabundance or storage, but also “states of deficiency” in that lack of salvage products from lysisimal processing may deprive cells of key metabolites. As naturally occurring states of “starvation-induced stress”, neurons in lysosomal disease may be undergoing chronically induced autophagy as well as upregulation of synthetic pathways to replenish unavailable metabolites. Such changes could have profound effects on neurons over time and may be causally linked to formation of axonal spheroids and ectopic dendrites. In order to understand these complex events which we believe will provide new insights for therapy development, we have emphasized the need to “think outside the organelle” – that is, to view lysosomal function from the view of “streams” involving endosomal, autophagosomal and salvage systems. Thus we have proposed that the lysosomal system is not simply a degradative site, but rather is a central metabolic coordinator that can exert significant influence over nearly every aspect of the life of the cell, from signal transduction (via endocytosis) to metabolic homeostatic regulation (via autophagy and salvage).

溶酶体疾病代表了一个复杂的遗传性疾病的复杂家族对溶酶体功能至关重要的特定蛋白质缺陷。至少有三分之二对大脑功能的重大影响，导致智力低下，痴呆，严重运动以及感觉障碍，精神病和行为改变以及癫痫发作。最多溶酶体疾病在婴儿期或童年时期发作，并急剧妥协，并且缩短受影响个人的生活。除了很少有效治疗有症状，可用。暴露的神经系统符号的复杂频谱患有溶酶体疾病的个体反映在类似的潜在多样性中分子和细胞异常。除了溶酶体储存之外，这些还包括甲壳虫发生和突触形成改变，轴突球形形成和选择性神经元变性。越来越认识到溶酶体疾病还表现出自噬以及异常蛋白质聚集的改变伴侣介导的自噬（CMA）和泛素蛋白体的参与系统（UPS）。这样的发现表明溶酶体中存在致病性级联反应类似于共同形式的神经变性的疾病，包括阿尔茨海默氏症和帕克森的疾病。重要的是，新的证据也表明溶酶体疾病不仅仅是过度保存或储存状态，还可以缺乏”缺乏裂解加工的打捞产品可能会剥夺细胞关键代谢产物。作为“饥饿诱导的压力”的自然存在的状态，神经元在溶酶体疾病中，可能正在经历长期诱导的自噬和上调复制不可用的代谢物的合成途径。这样的变化随着时间的流逝，可能会对神经元产生深远影响，并可能与轴突球体和生态树突的形成。为了理解这些我们认为，复杂的事件将为治疗开发提供新的见解，我们强调需要“在细胞器外思考”，也就是说，要查看溶酶体从涉及内体，自噬体和打捞的“流”的视图中的功能系统。我们建议溶酶体系统不仅是一种降解站点，而是中央代谢协调员，可以对从信号转导（通过内吞作用）到细胞生命的几乎每个方面代谢稳态调节（通过自噬和打捞）。