Pathogenic Mechanism of C9orf72 haploinsufficiency in ALS/FTLD: a road to therapeutic discovery
In this Hudson project, the team led by Dr. Robertson will pursue a comprehensive understanding of the normal functions of C9ORF72 and provide a better determination of whether loss of these functions via mutation may cause or contribute to ALS. One of the first discoveries about C9ORF72 was that it was a type of protein containing something called a DENN domain, which means it has function in normal movement of substances inside cells. Team member Dr. Peter McPherson, at McGill University, who discovered this unique function for DENN proteins, will further explore preliminary data that connects C9ORF72 to critical compartments in cells called lysosomes and their ability to recycle cellular components through a disposal process called autophagy. In recent years, numerous ALS genes have been connected to autophagy pathways. Furthermore, the team will examine other preliminary work showing that normal C9ORF72 may be necessary for proper movement of substances into and out of the nucleus, indicating that mutations in this gene causing ALS might have a dual effect on cells through loss and gain of function mechanisms. Finally, the team will study a completely unexplored potential function of C9ORF72 in a process called compensatory collateral sprouting, which is a function of neurons where they can regrow new connections at their ends when they get disconnected from muscles. Other work, including that of Canadian researchers, has indicated that this sprouting is impaired in ALS, but connection to C9ORF72 has not yet been made.
Janice Robertson , University of Toronto
Partners and Donors
ALS Society of Canada