Endosomal-Lysosomal Function in Neuronal Storage Disease

溶酶体疾病是一个复杂的家族，由近60种遗传相关疾病组成。 对溶酶体功能至关重要的特定蛋白质的缺陷。至少有三分之二的人 对大脑功能有显著影响，引起智力迟钝、痴呆，严重者运动功能减退， 和感觉障碍、精神病和行为改变以及癫痫发作。最 溶酶体疾病在婴儿期或儿童期发病， 缩短受影响个体的生命。有效的治疗方法很少，除了 有症状的，可用。表现出复杂的神经系统症状 溶酶体疾病的个体表现为类似的潜在多样性， 分子和细胞异常除了溶酶体储存，这些包括 外源性树突发生和改变的突触形成，轴突球体形成和 选择性神经元变性人们越来越认识到， 也表现出自噬的改变以及异常的蛋白质聚集， 分子伴侣介导的自噬（CMA）和泛素蛋白体的参与 系统（UPS）。这些发现表明在溶酶体中存在致病级联反应， 类似于常见形式的神经变性的疾病，包括 老年痴呆症和帕金森病重要的是，新的证据还表明， 溶酶体疾病不仅仅是过量或储存的状态，而且是“ 缺乏来自溶胞质加工补救产物的”缺陷“可剥夺细胞 关键代谢物作为自然发生的“饥饿诱导的应激”状态，神经元 在溶酶体疾病中，可能经历慢性诱导的自噬以及上调 合成途径来补充不可用的代谢物。这种变化 随着时间的推移，可能会对神经元产生深远的影响， 轴突球体和异位树突的形成。为了理解这些 我们相信这些复杂的事件将为治疗开发提供新的见解，我们 已经强调了需要“在细胞器之外思考”--也就是说， 从涉及内体、自噬体和补救的“流”的观点看功能 系统.因此，我们提出，溶酶体系统不仅是一个降解系统， 位点，而是一个中央代谢协调器，可以对 几乎细胞生命的每一个方面，从信号转导（通过内吞作用）到 代谢稳态调节（通过自噬和补救）。

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).