Endosomal lysosomal function in neuronal storage disease

溶酶体疾病代表了一组近60种单基因人类疾病，其由以下缺陷引起： 参与溶酶体系统正常功能的蛋白质类。最严重的影响是大脑， 进行性神经系统恶化数年至数十年，并致命。致病性级联反应 溶酶体功能障碍是非常复杂的，涉及各种各样的和不寻常的事件， 自噬对奇异和独特的（溶酶体疾病）“异位”树突生长的阻断， 皮质锥体神经元为了提供一个概念框架来理解这种复杂性， 2009年，他提出了“大溶酶体系统”的概念，将溶酶体置于细胞的中心舞台。 细胞的再循环过程，从内体和自噬体接收不同代谢物的“流” 途径。我们还强调了分解代谢产物从溶酶体中的“排出”，因为缺乏这种补救措施， 预计将导致代谢途径的前体不足，并可能上调 合成或诱导自噬以克服这种缺陷。重要的是，最近的发现 最值得注意的是，细胞代谢的主要调节者，哺乳动物的目标， 雷帕霉素（mTOR，特别是mTORC 1）锚定在溶酶体的表面。在这里，在无数的 功能，它控制转录因子的MITF家族的易位（例如，TFEB，TFE3）， 它们自身调节数百个参与自噬和溶酶体生物发生的基因。就谈这么多 现在有证据支持溶酶体作为细胞的“营养传感器”的观点，允许细胞协调 在高营养可用性期间的生长程序和在营养饥饿期间促进自噬。 我们相信这是迄今为止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。本提案的一个核心目标是 因此，为了分析mTOR在精心选择但不同的溶酶体疾病组中的功能， 这样做与我们早期和正在进行的研究一致，这些研究集中在溶酶体储存的异质性上， 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， 经历神经节苷脂的溶酶体储存的锥体神经元。因此，我们提出三个高度相互关联的 具体目标：首次进一步表征溶酶体胆积异质性以及p62聚集， 其与溶酶体的关系;第二，研究溶酶体储存对mTORC 1通路的影响 低激活和过度激活以及各自的后果;第三个是确定 改变的mTOR激活和树突复杂性的变化，包括所谓的“异位树突发生”。

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”.