Defining the Commander endosomal cargo sorting pathway in health and disease.

所有的人类细胞都是由一种叫做质膜的蛋白质和脂质的复杂混合物组成的外边界。它围绕着一个充满液体的三维空间，称为细胞质溶胶，其中包含额外的膜定义的隔室，每个隔室由蛋白质和脂质的独特组合组成。为了使细胞正常运作，蛋白质和脂质必须有效地运输到这个膜迷宫中正确的细胞器-细胞器是描述执行特定细胞功能的“膜定义室”的另一个术语。不足为奇的是，如果这种运输受到干扰，导致错误的蛋白质和脂质被输送到错误的细胞器，细胞器的功能就会受到不利影响，导致细胞、组织和有机体水平的生理失调。这反过来又导致了各种疾病的发展。因此，建立细胞实现受调节的蛋白质和脂质转运的机制是细胞生物学的一个主要挑战，对我们对人类疾病的理解有直接的影响。二十多年来，我们的实验室一直专注于描述控制蛋白质和脂质运输的机制细节，这是细胞膜迷宫的一个特定方面，称为内溶酶体网络。特别是，我们研究了一种古老的，高度进化的保守蛋白质复合体，称为Retromer。我们的研究，以及其他人的研究，正在定义逆转录酶的功能，这样做揭示了它在各种细胞过程中的重要性，这些过程对正常细胞功能至关重要。此外，很明显，Retromer的缺陷是多种人类疾病的基础，包括与年龄相关的神经退行性疾病，如帕金森病和阿尔茨海默病。事实上，小型和大型制药公司现在都认为Retromer是治疗这些疾病的可药物靶点。虽然Retromer的重要性越来越被认识到，但一个主要的未解决的问题涉及到不依赖于Retromer的蛋白质和脂质转运的机制。解决这个问题将构成该领域的一个重大进展：(i)这是实现对这些过程的详细机制理解的一个重要步骤；（ii）增加对机制的理解将进一步深入了解人类疾病中去调控的蛋白质和脂质转运；（iii）随着证据不断明确逆转录酶在神经退行性疾病中的去调控，理解逆转录酶依赖通路和不依赖通路的整合可能为利用内溶酶体网络的灵活性来补偿逆转录酶功能障碍的治疗策略提供基本思路。在目前的项目中，我们的目标是建立在我们最近在定义称为Commander的多蛋白组装结构及其在协调内体网络中不依赖于逆转录物的蛋白质和脂质运输中的功能方面的突破。Commander去调节是导致x连锁智力残疾和Ritscher-Schinzel综合征的原因。Ritscher-Schinzel综合征是一种严重的发育性疾病，影响骨骼发育、大脑功能和心血管系统。因此，对指挥官的研究将为这些疾病和其他人类疾病提供新的见解。在该计划中，我们描述了一个由国家和国际合作支持的整体方法，应用广泛但重点突出的一系列尖端技术来解决两个相互关联的目标：1)。Commander如何通过内体网络组织和调节蛋白质和脂质分选的基本机制问题2)。应用已获得的知识来确定Commander通路如何促进细胞、组织和生物体水平的生理，以及它如何在人类疾病中被解除调控。

All human cells are composed of an outer boundary that is defined by a complex mixture of protein and lipids called the plasma membrane. This encircles a fluid filled 3-dimensional space, termed the cytosol, which contains additional membrane defined compartments each composed of a unique combination of proteins and lipids. For cells to function normally, proteins and lipids must be efficiently transported to the correct organelle within this maze of membranes - organelle being another term for describing a 'membrane defined compartment' that performs a particular cellular function(s). Not surprisingly, if such transport is perturbed, so that the wrong proteins and lipids are delivered to the incorrect organelle, the function of that organelle can be adversely affected leading to de-regulated cell, tissue and organism level physiology. In turn this leads to the development of various diseases. Establishing the mechanisms through which cells achieve regulated protein and lipid transport is therefore a major challenge in cell biology with direct implication for our understanding of human disease.For over twenty years our laboratory has focused on describing the mechanistic details that control regulated transport of proteins and lipids with a specific aspect of the cell's membraneous maze termed the endolysosomal network. In particular, we have studied an ancient, highly evolutionary conserved protein complex called Retromer. Our research, and that of others, is defining Retromer function and in so doing is revealing its importance in a variety of cellular processes that are vital for normal cell function. Furthermore, it has become apparent that defects in Retromer underlie a variety of human diseases including age-related neurodegenerative diseases such as Parkinson disease and Alzheimer disease. Indeed, small and large Pharma now consider Retromer a druggable target for these diseases.While the importance of Retromer is increasingly recognised, a major unanswered question relates to the mechanism(s) of Retromer-independent protein and lipid transport. Addressing this question would constitute a major advance for the field: (i), it is an essential step towards achieving a detailed mechanistic understanding of these processes; (ii), increased mechanistic understanding will provide further insight into de-regulated protein and lipid transport in human disease; and (iii), as evidence continues to define Retromer de-regulation in neurodegenerative disease, understanding the integration of Retromer-dependent and Retromer-independent pathways is likely to provide rationale routes for therapeutic strategies that exploit the flexibility within the endolysosomal network to compensate for Retromer dysfunction.In the current programme, we aim to build on our recent breakthrough in defining the structure of a multi-protein assembly called Commander, and its function in orchestrating Retromer-independent protein and lipid transport within the endosomal network. Commander de-regulation is causative for X-linked intellectual disability and Ritscher-Schinzel syndrome, a severe developmental disease that affects skeletal development, brain function, and the cardiovascular system. The study of Commander will therefore provide new insight into these, and other, human diseases.In the programme, we describe a holistic approach supported by national and international collaborations, to apply a broad but focused array of cutting-edge techniques to address two inter-related aims: 1). The fundamental mechanistic question of how Commander functions to organize and regulate protein and lipid sorting through the endosomal network.2). Apply acquired knowledge to establish how the Commander pathway contributes to cell, tissue, and organism-level physiology, and how this is de-regulated in human disease.