AN EVOLUTIONARY APPROACH TO THE STUDY OF HUNTINGTIN, THE PROTEIN CAUSING HUNTINGTON’S DISEASE

Huntingtin is a protective protein for neurons and its mutation causes Huntington’s disease (HD). Studying normal huntingtin function is a means of better understanding the disease. One common approach to studying protein function is to look for similarly sequenced proteins whose function is already known in order to be able to test its activities by means of mutational analyses. This is not easy in the case of huntingtin because it is unlike any other known protein, and its primary sequence reveals little about its potential domains. Identifying evolutionarily older huntingtin molecules (called orthologues) and studying them bioinformatically and functionally may therefore be the only way of defining the evolution of huntingtin domains and, consequently, the function of the protein in the brain. Our hypothesis is that ancestral huntingtin arose to serve primordial and general functions, and only later acquired the additional functions that are particularly important for neurons. We propose: i) recovering huntingtin orthologues from key organisms that were crucial in the development of the nervous system, and analysing them bioinformatically; and ii) using complementation assays to test their ability to rescue the biological defects observed in huntingtin-devoid mice and mouse embryonic stem cells. This project will help us to understand if and how normal huntingtin function(s) are influenced by the presence of the disease mutation, and whether the biological defects observed in HD are due to loss of the protein’s neuroprotective activity.