Endosomal lysosomal function in neuronal storage disease

溶酶体疾病是一组近60种单基因人类疾病，由 参与溶酶体系统正常运作的蛋白质。最严重的影响大脑，导致 神经功能的进行性恶化会持续数年到数十年，而且是致命的。由以下原因引起的致病级联 溶酶体功能障碍非常复杂，涉及各种各样和不寻常的事件，从 阻止自噬生长奇怪而独特的(对溶酶体疾病)“异位”树突 皮质锥体神经元。为了提供一个概念性框架来理解这种复杂性，我们 2009年提出了“更大溶酶体系统”的概念，它将溶酶体置于 细胞的循环过程，接受来自内噬和自噬的不同代谢物 小路。我们还强调了溶酶体分解代谢产物的“外流”，因为缺乏这样的挽救。 预计会导致新陈代谢途径的前体不足，并可能上调 合成或诱导自噬来克服这种缺陷。重要的是，最近的发现给了我们 相信这一概念--最值得注意的是，细胞新陈代谢的主要调节者，哺乳动物的目标 雷帕霉素(MTOR)，特别是mTORC1，锚定在溶酶体表面。在这里，在无数的 功能，它控制MITF转录因子家族(例如，TFEB，TFE3)的易位， 它们自己调节着数百个参与自噬和溶酶体生物发生的基因。如此之多 现在有证据支持溶酶体是细胞的“营养感应器”的观点，允许细胞的协调 在营养高可用期间的生长计划，并在营养饥饿期间促进自噬。 我们认为，这是迄今发现的最重要的窗口，通过它可以调查 溶酶体疾病致病机制的复杂性。当前提案的一个核心目标是 因此，要分析mTOR在精心挑选但不同的溶酶体疾病组中的功能，并 这与我们早期和正在进行的专注于溶酶体存储异质性的研究是一致的， 自噬和p62聚集的失调，以及皮质上新的初级树突的独特生长 接受神经节苷脂溶酶体储存的锥体神经元。因此，我们提出了三个高度关联的 具体目标：首次进一步表征溶酶体存储的异质性以及p62聚集和 其与溶酶体的关系；第二，研究溶酶体储存对mTORC1途径的影响 低激活和过度激活及其各自的后果；第三，确定两者之间的关联 改变mTOR激活和树突状复杂性的变化，包括所谓的“异位树突状发生”。

Lysosomal diseases represent a group of nearly 60 monogenic human disorders caused by defects in proteins involved in normal functioning of the lysosomal system. Most severely impact the brain, cause progressive neurological deterioration over years to decades, and are fatal. Pathogenic cascades caused by lysosomal dysfunction are remarkably complex and involve diverse and unusual events ranging from the blockage of autophagy to the growth of bizarre and unique (to lysosomal diseases) “ectopic” dendrites on cortical pyramidal neurons. To provide a conceptual framework for understanding this complexity we developed in 2009 the concept of a “Greater Lysosomal System” which put the lysosome at center stage in the cell's recycling process, receiving “streams” of different metabolites from both endosomal and autophagosomal pathways. We also emphasized “egress” of catabolic products from lysosomes since lack of such salvage would be anticipated to result in deficient precursors for metabolic pathways and possible up-regulation of synthesis or induction of autophagy to overcome such deficiency. Importantly, recent discoveries give credence to this concept – most notably that a master regulator of cell metabolism, the mammalian target of rapamycin (mTOR, specifically mTORC1), is anchored at the surface of lysosomes. Here, among a myriad of functions, it controls the translocation of the MITF family of transcription factors (e.g., TFEB, TFE3) which themselves regulate hundreds of genes involved in autophagy and lysosomal biogenesis. Thus much evidence now supports the idea of the lysosome as the cell's “nutrient sensor”, allowing for orchestration of cell growth programs during periods of high nutrient availability and facilitating autophagy during nutrient starvation. We believe this is the most important window yet discovered through which to investigate the basis for the complexity of pathogenic mechanisms in lysosomal diseases. A central goal of the current proposal is therefore to analyze mTOR function across a carefully selected but diverse group of lysosomal diseases and to do so in concert with our earlier and ongoing studies focused on the heterogeneity of lysosomal storage, the dysregulation of autophagy and p62 aggregation, and the unique growth of new, primary dendrites on cortical pyramidal neurons undergoing lysosomal storage of gangliosides. Thus we propose three highly interlinked specific aims: The first to further characterize lysosomal storage heterogeneity as well as p62 aggregation and its relationship to lysosomes; the second to investigate the impact of lysosomal storage on mTORC1 pathway hypo- and hyperactivation and the consequences of each; and the third to determine the association between altered mTOR activation and changes in dendritic complexity, including so-called “ectopic dendritogenesis”.