Endosomal-Lysosomal Function in Neuronal Storage Disease

描述（由申请人提供）：最初设想的储存障碍被认为是由于在酸性环境中具有大量降解酶的端细胞器（溶酶体）内缺乏水解酶活性引起的。需要缺失酶降解的底物在三级溶酶体中积累，随着时间的推移，细胞质拥挤被认为会导致细胞功能受损，随后导致细胞死亡。鞘糖脂（GSLs）、粘多糖和糖蛋白被记录为需要溶酶体降解的典型底物，并且基于它们的积累（鞘糖脂病、粘多糖病、糖蛋白病等）建立了许多类型的贮藏病。许多这些储存化合物在大脑中显著表达，在大脑中，有限的神经发生和对长期神经元存活的需要被认为放大了细胞内储存的细胞毒性作用。重要的是，近年来的研究已经显著改变了对溶酶体贮积症的这种看法。首先，参与宿主非溶酶体和/或非酶功能的蛋白质现在已被证明是细胞内溶酶体储存的原因。其中一些蛋白质是加工或靶向溶酶体酶所必需的，但其他蛋白质是可溶性非酶溶酶体蛋白质或参与细胞器或底物运输的跨膜蛋白质。其次，溶酶体本身已不再被视为一个独立的终细胞器，而是与内体在动态连续体中的一个细胞成分。内体-溶酶体系统本身不仅对分子的降解和再循环至关重要，而且在信号转导事件和稳态控制机制中也至关重要。许多通过内体-溶酶体系统（GSLs，胆固醇等）转运的分子已被确定为特殊微结构域（“筏”）的组成部分，这些微结构域被认为是质膜中的信号平台。因此，溶酶体贮积病可能代表筏体功能紊乱的状态，筏体的贮积由内体和溶酶体内的“原木堵塞”组成。这种异常与大脑中的神经元储存特别相关，在大脑中，神经元不仅退化，而且经历了奇怪和独特的改变，从在某些神经元上萌发新的突触覆盖的异位树突到在其他神经元上形成不寻常的轴突异常。目前的建议将结合体内和体外分析以及神经元储存病的小鼠模型来测试专注于储存病的分子/细胞发病机制的特定假设。我们相信这些理解的进展将为潜在的治疗策略提供新的见解，并进一步阐明内体-溶酶体系统在健康和疾病中所起的关键作用。

DESCRIPTION (provided by applicant): Storage disorders as originally conceived were believed caused by an absence of hydrolytic enzyme activity within end-organelles (lysosomes) possessing numerous degradative enzymes in an acid milieu. Substrates requiring the missing enzyme for degradation accumulated within tertiary lysosomes and over time cytoplasmic crowding was believed to lead to compromise in cell function followed by cell death. Glycosphingolipids (GSLs), mucopolysaccharides and glycoproteins were documented as typical substrates requiring the lysosome for degradation and numerous classes of storage diseases were established on the basis of their accumulation (glycosphingolipidoses, mucopolysaccharidoses, glycoproteinoses, etc.). Many of these storage compounds were prominently expressed in brain where limited neurogenesis and the need for long-term neuronal survival were believed to amplify the cytotoxic effects of intracellular storage. Importantly, studies of recent years have significantly altered this view of lysosomal storage disorders. Firstly, proteins involved in a host of non-lysosomal and/or non-enzymatic functions have now been documented as causes of intracellular lysosomal storage. Some of these proteins are essential for processing or targeting of lysosomal enzymes but others are soluble non-enzyme lysosomal proteins or are transmembrane proteins involved in organelle or substrate trafficking. Secondly, the lysosome itself has come to be viewed not simply as an independent end-organelle, but rather as a cell component in dynamic continuum with endosomes. The endosomal-lysosomal system has itself been established as critical not only for the degradation and recycling of molecules but also in signal transduction events and homeostatic control mechanisms. Many of the molecules transiting through the endosomal-lysosomal system (GSLs, cholesterol, etc.) have been identified as constituent parts of specialized microdomains ("rafts") believed to act as signaling platforms in the plasmalemma. Consequently, lysosomal storage diseases may represent states of disordered raft function with storage consisting of "log jams" of rafts within endosomes and lysosomes. Such abnormalities are particularly relevant to storage in brain where neurons do not simply degenerate but undergo bizarre and unique alterations ranging from sprouting of new, synapse-covered ectopic dendrites on some classes of neurons to formation of unusual axonal abnormalities on others. The current proposal will use a combination of in vivo and in vitro analyses and murine models of neuronal storage diseases to test specific hypotheses focused on the molecular/cellular pathogenesis of storage diseases. Such advances in understanding we believe will provide new insights into potential treatment strategies and further elucidate the critical role played by the endosomal-lysosomal system in both health and disease.