Every human cell contains a microscopic postal system called the endosomal network, and a protein complex named Commander is the sorting machine that directs cargo to the right internal compartments—when it fails, proteins end up in the wrong place, and disease follows. This matters because scientists understand one sorting machine, Retromer, but have known almost nothing about a second, independent pathway that Commander controls. Without that knowledge, the picture of how cells manage their internal traffic is incomplete. Commander mutations directly cause X-linked intellectual disability and Ritscher-Schinzel syndrome, a severe developmental disorder affecting the skeleton, brain, and heart. This is fundamental cell biology. The researchers will map Commander’s structure and mechanism, then test how its failure disrupts whole tissues and organisms. If successful, the work will reveal why certain developmental and neurological diseases arise from a single broken sorting step. It may also show how cells could compensate for Retromer defects in Parkinson’s and Alzheimer’s disease—opening routes for therapies that exploit the network’s built-in flexibility. No immediate clinical tool will emerge, but understanding this ancient sorting pathway is a prerequisite for designing one.
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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.
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