GLT8D1: new gene identifies novel disease mechanism

MND Association-supported clinical fellow Dr Johnathan Cooper-Knock, and a PhD student Tobias Moll, report mutations in a new MND gene which has uncovered a previously unknown disease mechanism. The new MND causing gene holds instructions for a class of proteins, called glycosyltransferase (GLT8D1), which has not previously been associated with neurodegeneration.

During the experiments, published in the journal Cell Reports, the research team read the genetic code from two related patients with an unknown familial (inherited) form of MND and found a change in the gene that makes an enzyme called GLT8D1. They went on to examine a larger sample of 103 people with inherited MND and found that five of these also had this gene abnormality, indicating that this change causes MND. Because the enzyme and its mechanism have never previously been associated with MND, this study has uncovered a new genetic and biological cause of the disease.

This is another piece of the MND puzzle, identifying a new avenue to explore which will hopefully identify further key landmarks in the biology of motor neurons and MND.

Dr Cooper-Knock, and Tobias Moll are both based in Prof Pamela Shaw’s lab at the Sheffield Institute for Translational Neuroscience (SITraN) and the NIHR Sheffield Biomedical Research Centre (BRC). Tobias is conducting his PhD studies with the NIHR Sheffield BRC Junior Academy under the supervision of Dr Cooper-Knock and Professor Shaw. Additional authors from various consortia have collaborated to confirm this discovery, and people with MND have generously provided samples for the international consortium Project MinE.

Project MinE is part-funded by the MND Association and is the largest MND gene collection project in the world. Thsi initiative, amongst other consortia, provide researchers with the opportunity to sequence DNA and identify new MND risk genes.

Watch Dr Cooper-Knock talking about the importance of Project MinE, at the 29th International Symposium on ALS/MND in Glasgow:

How did they find it?

The team performed sequencing of the exome (DNA that holds the instructions for proteins) in autosomal dominant familial MND patients. ‘Autosomal dominant’ means that a person only needs to inherit one copy of the gene, from either the mother or the father, for them to have the potential for disease – therefore a 50/50 chance of inheriting if one parent had MND. The initial sequencing identified five possible gene changes that may cause MND and further narrowing down of these changes revealed one causative gene – GLT8D1.

What do we know about GLT8D1?

According to the paper, GLT8D1 is a member of ‘glycosyltransferase family 8’ and is thought to play a role in the chemistry that goes on between the substances in the cell. If this cannot function properly then problems arise.

Glycosyltransferases represent a large family of enzymes. Many glycosyltransferases are involved in manufacturing of small molecules, called gangliosides, that are abundant in the central nervous system (the brain and spinal cord) and are suggested to participate in various neurodegenerative processes. Altered levels of gangliosides have been found in animal models of MND and in brain tissue of people with MND, suggesting they play an important role, but as yet we don’t know if this is cause or effect. The research team are currently working to determine whether GLT8D1 is involved in the manufacturing of these gangliosides.

What are the effects of these GLT8D1 mutations?

Mutations in a gene normally change the function of the protein that is made from the gene. To test if the mutation in GLT8D1 changed the function of the protein that is made from it, the team tested the effect of the GLT8D1 mutations in experiments in the laboratory. The team showed that the gene did cause a change in the protein, and that the change in protein would have an effect on neurons as occurs in the disease.

They found that the mutation caused toxicity in neuronal and non-neuronal cells, and the relative toxicity of the mutations mirrors the clinical severity in people with MND. When the mutant protein is put into an animal model, in this case zebrafish, the mutant protein also reduces locomotion (swimming ability) in the fish, which suggests a motor neuron problem.

In our cells, the GLT8D1 gene makes a protein, and this protein is an enzyme. Enzymes convert one substance to another in our bodies and it is possible to measure the rate of these conversions in lab experiments called assays. To see if the mutations identified in people with MND may modify the activity of the enzyme, the team collected and measured enzyme activity of the purified protein using an assay. They discovered that mutations reduce the enzyme activity of GLT8D1 and suggested that it is this altered activity that might impact on the health of neurons, therefore providing a promising new avenue to target a potential treatment, perhaps by restoring the activity of the enzyme.

This work, which identified a new causative gene in MND, is an important breakthrough in the fight against MND. Each time a gene is associated with MND, we have more information and new areas to investigate, bringing us closer to understanding the biology of the disease and uncovering potential areas to target in the development of new treatments.

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