Project goal: Investigating the link between toxic repeat RNA and spinocerebellar ataxias.
Many hereditary ataxias, such as SCA10, SCA31 and SCA36, are caused by specific types of genetic mutations known as nucleotide-repeat expansions. This type of mutation is caused by errors during the normal process of copying a cell’s DNA: the copying machinery makes editing mistakes and adds many copies (often hundreds to thousands) of nucleotide repeats to a gene. Such a nucleotide-expanded gene will, in turn, produce an mRNA1 containing the corresponding nucleotide repeats and these aberrant mRNA molecules will accumulate in ball-shaped structures known as ‘repeat mRNA foci’ in the cell nucleus. These mRNA foci are toxic to the cell and are thought to act as molecular sponges that will attract specific cellular proteins and perturb their normal functions. At present, it is not known exactly which proteins are trapped in these foci, or precisely how they are formed.
Our project aims to identify and study the proteins that are captured by foci in SCA10, SCA31 and SCA36 ataxias. Among the proteins identified, we will determine the best targets for developing therapies. For example, if one of the proteins plays a role in the accumulation of repeat mRNAs with long additions, it could become the target of a therapy aiming to decrease the quantity of this protein and thus hope to reduce mRNA accumulation and foci formation.
This is an important project because, to date, research into SCA10, SCA31 and SCA36 ataxias is scarce. Our project will not only significantly advance our understanding of these diseases, enabling therapeutic discoveries, but it will also contribute to our understanding of RNA metabolism in health and disease in general, which could be applied to other diseases.
1mRNA stands for messenger RNA: the link between DNA and protein. The molecule that contains the instructions for building a protein.