Defining the role of retromer-like in endolysosomal cargo sorting in health and disease.

所有人类细胞都由一个外部边界组成，这个外部边界是由一种称为质膜的蛋白质和脂质的复杂混合物所定义的。这包围了一个充满流体的三维空间，称为胞浆，它包含额外的由膜定义的隔室，每个隔室由蛋白质和脂类的独特组合组成。为了细胞正常运作，蛋白质和脂类必须被有效地输送到这个错综复杂的细胞膜中的正确细胞器--细胞器是另一个术语，用于描述执行特定细胞功能的“膜定义的隔室”(S)。毫不奇怪，如果这种运输受到干扰，以至于错误的蛋白质和脂类被传递到错误的细胞器，该细胞器的功能可能会受到不利影响，导致细胞、组织和生物体水平的生理学失控。反过来，这又会导致各种疾病的发展。因此，建立细胞实现蛋白质和脂类调节运输的机制是细胞生物学中的一个主要挑战，它直接影响我们对人类疾病的理解。十多年来，我们的实验室一直致力于描述控制蛋白质和脂类调节运输的机制细节，以及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、高度进化保守的蛋白质复合体，称为逆聚体。我们和其他人的研究正在定义逆转录功能，并在这样做的过程中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，逆转录体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。虽然逆转聚体的重要性得到了越来越多的认识，但一个重大的悬而未决的问题涉及到逆转录非依赖蛋白质和脂肪运输的机制(S)。解决这一问题将是该领域的一大进步：(1)这是实现对这些过程的详细机制理解的关键一步；(2)增加对机制的理解将进一步洞察人类疾病中去调控的蛋白质和脂肪运输；以及(Iii)随着证据继续定义神经退行性疾病中逆转聚体的去调节，了解逆转录依赖和逆转录非依赖途径的整合可能为利用内溶体网络中的灵活性来补偿逆转录功能障碍的治疗策略提供基本路线。在当前的计划中，我们的目标是在我们最近发现的以前未被识别的蛋白质组装的基础上，协调内溶体网络中的逆转录非依赖性蛋白质和脂肪的运输--我们将其称为“逆转录聚体样”。从现有的文献来看，逆转录-样失调节和神经退行性疾病之间似乎有联系，在初步研究中，我们发现了与高胆固醇血症(高胆固醇)的额外联系。因此，对类逆转录病毒的研究将提供对这些和其他人类疾病的新见解。在该方案中，我们描述了一种得到国家和国际合作支持的整体方法，以应用广泛但有重点的尖端技术来解决两个相互关联的目标：1)。最根本的问题是，逆转聚体如何作为一台“机器”，调节蛋白质和脂类在内溶酶体网络中的分选。应用已获得的知识来确定体内细胞、组织和生物体水平的生理学如何需要逆转录体样的活性，以及在人类疾病中如何解除这种调节。

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 ten 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. 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 identification of a previously unrecognised protein assembly that orchestrates retromer-independent protein and lipid transport within the endolysosomal network - we have termed this 'retromer-like'. From the existing literature there appears to be links between retromer-like de-regulation and neurodegenerative disease, and in preliminary studies we have revealed additional links to hypercholesterolaemia (high blood cholesterol). The study of retromer-like 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 question of how retromer-like functions as a 'machine' to regulate protein and lipid sorting through the endolysosomal network.2). The application of acquired knowledge to define how retromer-like's activity is required for in vivo cell, tissue and organism-level physiology and how this is de-regulated in human disease.