The Role of Dolichol in Linking Glycosylation, Lipid Homeostasis and Human Disease

Objetivo

A major bottleneck in the development of preventative therapies to help us age healthily is the identification of molecular mechanisms underlying age-related conditions such as atherosclerosis and neurodegeneration. Some of our most revolutionary treatments for these conditions, such as statins, target the metabolism of lipids (e.g. triglycerides or cholesterol). In contrast, the lipid dolichol has been almost completely overlooked, despite its critical importance to glycosylation and accumulation in all tissues with age, in neurodegenerative disease, and in atherosclerotic plaques.
We recently discovered new complexities in dolichol metabolism, including novel enzymatic steps and metabolites, that may play a role in the pathology of these processes. Yet, our knowledge of the subcellular organisation, enzyme repertoire and biological effects of dolichol metabolism is still incomplete. Furthermore, little is known about dolichol degradation or transport either inside the cell or around the body. The goal of DOLIGOAL is to remove these roadblocks.
To do this, we will characterise the subcellular architecture of dolichol biosynthesis and aim to identify the enzymes involved in esterifying dolichol for storage. Next, we will study intracellular transport or extracellular efflux pathways. We will also follow-up preliminary data indicating that the disruption of dolichol metabolism transcriptionally modulates cholesterol synthesis, indicating novel regulatory mechanisms. Lastly, the relevance of these findings for human disease will be explored.
This ambitious multidisciplinary project ties together several aspects of cell biology and metabolism, requiring diverse analytical techniques. Fully understanding dolichol metabolism, transport and cellular functions could unlock paths to novel treatments for both rare and common diseases.

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