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Researching rare disorders: NGLY-1, the first disorder of deglycosylation

Updated Wednesday 8th March 2017

What happens when our cells can’t get rid of the waste products they produce?  Working on a project inspired by the passion of the rare disease community, Open University PhD student Sarah Needs explains:

Sugars and Proteins

Sugar and proteins in the context of the cell are very different to the sugar and proteins we think of as being in our diet. The body is made up of cells and in these cells are many different proteins. These proteins are essentially the workhorses of the cell that regulate and control the body's function. When proteins are first synthesised a sugar chain called a glycan is added to the protein in a process called glycosylation.

Protein shape is crucial to the specific function of the protein and the glycosylation step helps to stabilise the protein and ensure it has its correct shape which is crucial to its function. However, our cells are not 100% efficient in this process and some proteins fail to fold correctly. Therefore, these misfolded proteins needs to be degraded or they can have detrimental effects on the cell.

The degradation of misfolded proteins is mediated by the N-glycanase protein which removes the glycan from the surface of misfolded proteins, a process called deglycosylation. Without this proteins cannot be degraded efficiently and build up in a mass in the cell. This build-up of waste proteins in the cell can be detrimental to the cell, for example some of the most prevalent disorders causing dementia, such as Alzheimer’s, Parkinson’s and Huntington’s are also caused by a build-up of misfolded proteins in the brain.

What is NGLY1 deficiency?

NGLY1 deficiency is a rare genetic disorder caused by mutations in the N-glycanase gene. This means that patients with this mutation produce little to no N-glycanase protein. N-glycanase is involved in the recycling of proteins and without this old or non-functional proteins build up in the cell, which is toxic. My research focuses on protein aggregation when this deglycosylation is impaired, and how the cell copes with this aggregated material.

NGLY1 is the first and so far, only disorder of deglycosylation discovered. N-glycanase is active in all cells in the body and the symptoms caused by its loss can affect the whole body. Typical symptoms include difficulty in walking and talking, reduced cognitive skills as well as loss of muscle tone and a lack of tears.

It was first identified in 2012, and to date there have been only 55 patients identified with this disorder worldwide with ages ranging from a few months old to those in their 20’s.  Currently there is no cure for this disorder and all medications focus on treating the symptoms. 

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