Abnormalities in the C9ORF72 gene are one of the major genetic causes of FTD. Until recently it has not been clear how these expansions (where part of the gene is repeated hundreds or thousands of times) cause FTD. However, in the last few months, several independent research groups have demonstrated the toxicity of a specific set of proteins produced in patients with C9ORF72 expansions.
The majority of neurodegenerative diseases are sporadic in nature, occurring fairly randomly throughout the population, especially in later life. However, in rare instances certain individuals can carry mutations in genes, which directly and inevitably cause a particular disease and can be passed on through families. One such gene called C9ORF72 (its name derives from its position in the human genome) was discovered in 2011, and patients with mutations in this gene can go on to develop symptoms of either FTD or motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS). The discovery of these C9ORF72 mutations was exciting both in the sense that studying this gene may provide insight into why sporadic forms of these diseases occur, but also because of the high number of patients who carry the mutation. It is estimated that approximately 5-10% of what were previously thought to be sporadic patients carry a mutation in C9ORF72.
The mutation in question is always an expanded piece of very repetitive DNA, which may lead to nervous system damage in a number of ways. DNA is the template used by cells to produce the proteins necessary for the cell to function. In order for the proteins to be constructed from amino acid building blocks in the correct manner, DNA is first transcribed into a temporary messenger molecule called mRNA, which is then read by the cell’s ribosomes to produce protein. The repetitive nature of the DNA in the C9ORF72 mutation means that repetitive mRNA is produced, which is read by the cell into several very repetitive proteins, consisting of a pair of amino acids repeated over and over. This repetitive mRNA and the different repetitive protein species it produces all have the potential to be toxic.
In order to separate out the mRNA and different proteins, recently, several teams of researchers have used a strategy of artificially creating genes which produce individual repetitive toxic proteins but have the an underlying DNA sequence which does not produce the repetitive interim mRNA molecules. By turning on these synthetic genes in different cell types, or in the nerve cells of fruit flies, several independent groups of researchers have demonstrated that repetitive proteins which contain the amino acid arginine appear to have the greatest propensity to be toxic.
To try to work out what makes these arginine-rich proteins toxic, researchers like Davide Trotti at Thomas Jefferson University have used fluorescent labels to demonstrate that arginine-rich proteins accumulate within a structure called the nucleolus in cells, which is required for cells to make proteins properly. Additionally Zheng Ying’s group at Soochow University have demonstrated that the toxic arginine-rich proteins can bind to several nucleolar components, potentially preventing them from functioning normally, and causing cellular damage.
These findings suggest that interventions that limit the production of toxic proteins from the C9ORF72 gene in human patients may serve as a potential treatment for this genetic form of disease. Additionally, if further evidence is found that nucloeolar dysfunction is what directly causes neurodegeneration in C9ORF72 patients, then this could give insight into the types of mechanism at play in sporadic forms of FTD.
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