Olivia Rezek MSc AMRSB, a Laboratory Scientist at WideCells, reviews the latest research into a gene mutation which results in an abnormal number of DNA sequence repeats:
G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. Simone et al., 2018
Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two rapidly progressive neurodegenerative disorders which seem to have an underlying genetic link, leading to an overlap of the conditions in patients.
FTD is a condition characterised by the progressive neurodegeneration of the frontal and/or temporal lobes in the cerebral cortex of the brain, resulting in symptoms affecting behaviour, emotion, social awareness and language.
ALS is a disease of the motor neurons, characterised by the degeneration of nerve cells which control voluntary muscle movement – resulting in muscle wastage and weakness, slurred speech and eventually, the inability to swallow or breathe.
In 2011, a research group reported that a mutation in a particular gene, known as C9ORF72, is associated with both FTD and ALS.
This mutation has been defined as an expansion of a specific DNA sequence in a part of the C9ORF72 gene, which results in an abnormal number of DNA sequence repeats.
People with the standard form of the gene usually carry less than 30 repeats of the DNA sequence, whereas people carrying pathogenic mutations, have more than 30 repeats. This mutation interferes with the normal function of the gene. Although it is not exactly clear how this leads to pathogenesis, research has pointed to a consequential over-activation of the protein product derived from C9ORF72. This causes a toxic build-up, or aggregation, of proteins in neurons, which is thought to lead to cell death.
A research group from University College London investigated whether it was plausible to target a key step of C9ORF72 gene expression – the process where the information coded for by the gene, is being synthesised into the functional gene product – in attempts to reduce the pathological effect of this C9ORF72 repeat expansion.
To do this, the group used small molecules, which are organic compounds used as drugs to regulate biological processes, to target the C9ORF72 gene expression process, and effectively stabilise the abnormal protein products generated by the C9ORF72 repeat expansion.
