Every cell in the human body relies on a microscopic sorting machine to deliver proteins and fats to the correct internal compartments, and a newly discovered version of this machine—called retromer-like—may be failing in both neurodegenerative diseases and high cholesterol. For over a decade, researchers have studied the original sorting complex, retromer, and linked its breakdown to Parkinson’s and Alzheimer’s diseases. But a major gap remained: how do cells sort cargo when retromer is not involved? The team recently identified retromer-like, a separate protein assembly that handles this alternative route. This project will first determine exactly how retromer-like works as a molecular machine, then test how its failure disrupts cells, tissues, and whole organisms. This is fundamental cell biology. If successful, it will provide a mechanistic blueprint for how cells compensate when retromer goes wrong. That knowledge could eventually guide therapeutic strategies—for example, drugs that boost retromer-like activity to bypass retromer defects in neurodegenerative disease, or that correct its role in cholesterol metabolism. Past fundamental work on similar sorting complexes has already opened unexpected avenues for treating genetic disorders, making this a plausible path toward future treatments.
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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 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.
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