From a rare disease to the discovery of one of the first steps in glycosylation

In a nutshell

• Almost half of our proteins carry sugars on their surface, attached in a process known as glycosylation.
• Dolichol is a compound that plays a central role in glycosylation and accumulates as the brain ages.
• Following the discovery of a very rare disease, researchers have revealed new players in the process that enables our cells to synthesise dolichol. This represents an unexpected complexity in the early stages of glycosylation.
• These discoveries were made by a team from UCLouvain in collaboration with teams from Leuven and Lille, and are published on 30 May 2024 in the scientific journal Cell.

A research team from the Institut de Duve (UCLouvain) and WELBIO, in collaboration with teams from Leuven and Lille, has just identified new players in the pathway that enables our cells to synthesise dolichol, a compound that plays a central role in the transfer of sugars to proteins and that accumulates in our brains as we age. The researchers also describe an ultra-rare disease that develops when one of these new players is deficient. This advance in our knowledge should make it possible to treat the patients in question more effectively, but it could also help us to understand the mechanisms involved in more common diseases that occur during the ageing process. The study is published in Cell.

Almost half of our proteins carry sugars on their surface, which are attached in a process called glycosylation. This influences their function and stability. Dolichol is a particular compound that we have in all our cells in very small quantities and which is chemically related to rubber. It is found in the center of intracellular membranes and plays a very important role in the binding of sugars to proteins.

Despite its complexity, we are able to synthesise this molecule through a series of enzymatic steps that, until recently, we thought we knew all the details. This was not true. A team from UCL, in collaboration with teams from Leuven and Lille, has demonstrated that the final stages of synthesis involve one enzyme and two metabolites more than previously thought. As a result of mutations in its gene, the enzyme in question is deficient in a new, ultra-rare disease, which these researchers are also describing.

This advance in our knowledge should make it possible to treat the patients in question more effectively, but it could also help us to understand the mechanisms involved in the much more common degenerative diseases that occur during the ageing process. Dolichol is an exceptional molecule in that its concentration increases progressively in the brain from birth into old age - and we don't know why, or whether this is a good thing or a bad thing. There is no doubt that behind these two questions lies an as yet unknown role for dolichol that needs to be identified in order to gain a better understanding of certain degenerative diseases. The results obtained open up new avenues for studying these questions.

Article describing this research

A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis

Wilson MP, Kentache T, Althoff CR, Schulz C, de Bettignies G, Mateu Cabrera G, Cimbalistiene L, Burnyte B, Yoon G, Costain G, Vuillaumier-Barrot S, Cheillan D, Rymen D, Rychtarova L, Hansikova H, Bury M, Dewulf JP, Caligiore F, Jaeken J, Cantagrel V, Van Schaftingen E, Matthijs G, Foulquier F, Bommer GT

Cell 2024, 187, 1–17