Endosomal-Lysosomal Function in Neuronal Storage Disease

溶酶体疾病代表了一个由近60种疾病组成的复杂家庭，这些疾病由遗传联系在一起 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 严重影响大脑功能，导致智力低下、痴呆症、严重运动 感觉障碍，精神错乱和行为改变，以及癫痫。多数 溶酶体疾病起病于婴儿期或儿童期，并极大地损害和 缩短受影响个人的生命。几种有效的治疗方法，除了 有症状的，是可用的。复杂的神经症状表现为 由溶酶体疾病的个体所反映的相似的多样性的潜在 分子和细胞异常。除了溶酶体存储外，还包括 广泛性树突发生和突触形成改变，轴突球体形成和 选择性神经元变性。人们越来越认识到溶酶体疾病 也表现出自噬的改变以及蛋白质的异常聚集 伴侣介导的自噬和泛素蛋白酶体的参与 系统(UPS)。这些发现表明溶酶体中存在致病性级联反应。 类似于普通形式的神经退行性变的疾病，包括 阿尔茨海默氏症和帕金森氏症。重要的是，新的证据也表明 溶酶体疾病不是简单的过多或储存状态，也是“ 缺乏来自裂解液处理的回收产物可能会剥夺细胞 关键代谢物。作为“饥饿应激”的自然发生状态，神经元 在溶酶体疾病中，可能正在经历慢性诱导的自噬和上调 补充不可用代谢物的合成途径。这样的变化 可能会随着时间的推移对神经元产生深远的影响，并可能与 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发展提供新的见解，我们 强调了“在细胞器之外思考”的必要性--也就是说，要观察溶酶体 从涉及内吞体、自噬和挽救的“流”看功能 系统。因此，我们提出溶酶体系统不是简单的降解物。 站点，而是中央代谢协调器，可以对 细胞生命的几乎方方面面，从信号转导(通过内吞作用)到 代谢平衡调节(通过自噬和回收)。

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).