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June MND Research Article summary – Ben Hall, PhD student, University of Sheffield

June 2020

Ben Hall, a PhD student at the University of Sheffield kindly provided a lay summary for an MND research article recently published.

    Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72 (13/04/2020; doi: 10.1038/s41593-020-0619-5)

One of the major causes of ALS/MND is a mutation in a gene known as C9ORF72, which is present in around 10% of patients, and is toxic to the cells of people with the mutation. In a healthy individual the C9ORF72 gene would ordinarily provide a template for the cell to engineer a protein that carries out several roles in a cell. Mutation in the C9ORF72 gene can cause toxicity to a cell in two ways. It can cause a toxic ‘gain of function’ in which the template provided by the gene engineers a protein whose function is altered in a way that is detrimental to the cell, thus causing toxicity. Alternatively, the mutation could prevent the protein from carrying out its usual function also causing toxicity. The exact mechanism, whether it be via a gain or loss of function of the C9ORF72 protein is currently unknown.

In a study by Zhu et al., (2020), the researchers set out to investigate the mechanism via which a C9ORF72 mutation can cause toxicity. To do this they used gene editing techniques to ‘inactivate’ the C9ORF72 gene in mouse models that had the MND causing mutation. They found that inactivating the mutated C9ORF72 gene accelerated death in these mice that also had a reduced ability to perform normal movement and demonstrate cognitive ability (the mice were tested on their ability to complete a maze). These mice also showed increased motor neuron death, coinciding with an increase in activation of astrocytes and microglia (cells that provide a supporting role to motor neurons and become ‘activated’ in response to neuron damage). The mutation also caused a reduction in levels of autophagy (a cellular process that removes malfunctioning proteins).

These findings allowed the researchers to conclude that the C9ORF72 gene may cause motor neuron death through a loss of protein function AND a gain of function, an important finding in the search for effective MND treatments. This evidence demonstrated in the study also supports the hypothesis for an ongoing phase 1 clinical trial, potentially benefiting patients within years.

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