Project 452179

Many degenerative diseases that affect muscles and/or the nervous system are caused by a similar type of genetic mutation involving the amplification of repetitions of short stretches of DNA bases, called nucleotide repeats, in the genome of affected individuals. This includes diseases such as mytotonic dystrophy type 1 (CTG repeats) or type 2 (CCTG repeats), amyotrophic lateral sclerosis/ALS (GGGGCC repeats) and Huntington's diseases (CAG repeats), which can be caused by recurrent repeat expansions within specific genes. These DNA nucleotide repeats are often converted into repeat-containing RNA molecules, which are highly toxic to the cell due to their propensity to act as molecular sponges that will attract proteins that bind to RNA and inactivate their normal functions. This molecular sponging process is thought to block several essential cellular house-keeping functions, thus underlying the cellular degeneration observed in these diseases. In this project, we aim to test whether different types of toxic repeat-containing RNAs have similar sponging properties, i.e. do they interfere with cellular functions in similar of different ways. We will address this important question by using cutting-edge experimental approaches and unique tools that we developed to identify cellular proteins that interact with each type of repeat RNA. We will also conduct genetic studies in 'diseases model' fruit flies that exhibit muscle and nervous system degeneration when they express repeat RNAs associated with specific human diseases. Altogether, we believe that this work will help illuminate the similarities and differences in the sponging properties of various types of toxic repeat RNAs, which is important in order to devise ways to treat these diseases.