Endosomal-Lysosomal Function in Neuronal Storage Disease

描述（由申请方提供）：溶酶体胆积症由影响正常溶酶体功能所必需的蛋白质的广泛遗传突变引起。已经记录了不少于50种蛋白质的缺陷导致溶酶体功能障碍，并且与溶酶体疾病相关的新蛋白质不断被发现。已知溶酶体疾病影响许多组织和器官，其中最显著地影响大脑，导致严重的认知障碍，包括痴呆、共济失调、震颤和相关的运动系统功能障碍、失明、耳聋和其他感觉障碍、精神病发作和癫痫发作。这种复杂的一系列临床特征反映在多种潜在的分子和细胞异常中，包括异位树突发生、神经轴突营养不良、蛋白质聚集状况（包括tau蛋白病、神经变性等）。我们认为，这种多样性的影响特点的储存疾病影响大脑是最好的解释，超越溶酶体，更广泛的异常内体，逆转录酶，自噬体，和蛋白酶体系统，我们称之为“大溶酶体系统”。重要的是，也有越来越多的证据表明，溶酶体疾病不仅是储存状态，而且也是缺乏状态，未能从患病的溶酶体中挽救降解的底物，导致其他代谢过程的关键前体短缺。总而言之，溶酶体疾病的这一新概念强调了将溶酶体及其加工流不仅仅视为被动消化过程的重要性，而是将其视为从信号转导到稳态调节的深远细胞事件中不可或缺的参与者。为了进一步了解影响大脑的溶酶体疾病，并阐明更大的溶酶体系统作为正常神经元中的代谢调节因子的作用，我们提出了一系列研究，旨在测试试图解释许多溶酶体疾病的两个最有据可查但神秘的特征-异位树突状细胞生成和神经轴索营养不良的发展的假设。我们相信，这些致病途径的描述和溶酶体系统的潜在作用将为理解和治疗具有相似特征的常见神经退行性疾病打开大门，从脆性X染色体和其他树突状病变到阿尔茨海默病等痴呆症。

DESCRIPTION (provided by applicant): Lysosomal storage disorders result from a wide spectrum of genetic mutations affecting proteins integral to normal lysosomal function. Defects in no less than 50 proteins have been documented to cause lysosomal dysfunction, and new proteins linked to lysosomal disease continue to be discovered. Lysosomal diseases are known to affect many tissues and organs with most significantly impacting the brain, leading to severe cognitive impairment including dementia, ataxia, tremors and related motor system dysfunctions, blindness, deafness and other sensory impairments, psychotic episodes and seizures. This complex array of clinical features is reflected in a diversity of underlying molecular and cellular abnormalities, including ectopic dendritogenesis, neuroaxonal dystrophy, protein aggregation conditions including tauopathy, neurodegeneration, and so forth. We believe that this diversity of impact characteristic of storage diseases affecting brain is best explained by looking beyond the lysosome to broader abnormalities in endosomal, retrosomal, autophagosomal, and proteasomal systems, what we refer to as the 'Greater Lysosomal System'. Importantly, there is also increasing evidence that lysosomal diseases are not simply states of storage but are also states of deficiency, with failure to salvage degraded substrates from diseased lysosomes leading to shortages of critical precursors for other metabolic processes. Taken together, this new concept of lysosomal disease stresses the importance of viewing the lysosome and its processing streams not simply as a passive digestive process but rather as an integral player in far reaching cellular events, from signal transduction to homeostatic regulation. In order to advance understanding of lysosomal diseases affecting brain and to illuminate the role of the greater lysosomal system as a metabolic regulator in normal neurons, we propose a series of research aims to test hypotheses that attempt to explain the development of two of the most well documented but enigmatic features of many lysosomal diseases - ectopic dendritogenesis and neuroaxonal dystrophy. Delineation of these pathogenic pathways and the underlying role of the lysosomal system we believe will open the door to understanding, and treating, commoner neurodegenerative diseases that share similar features, from Fragile X and other dendritopathies to dementias like Alzheimer's disease.