$1.6 million awarded to Dr. Janice Robertson, a professor at University of Toronto.
In 2011, scientists discovered that hereditary mutation of a previously unstudied gene called C9ORF72 was the most prominent cause of both ALS and frontotemporal dementia (FTD). These mutations were found in both hereditary (familial) and non-hereditary (sporadic) forms of the disease and comprise about one third of all cases.
Since that discovery, ALS researchers have aimed to understand the normal function of C9ORF72, determine how mutations in the gene can cause the disease and create animal and cellular models to study it. In 2015, Dr. Janice Robertson published a landmark paper that demonstrated the existence of two different forms of C9ORF72 protein, including one that localized to the outer layer of the cell’s command centre called the nucleus. This was the first indication of what would become a breakthrough discovery by three teams independently showing that mutations in C9ORF72 disrupt the movements of critical substances into and out of the nucleus.
When a mutation in a gene causes ALS, it may do so by removing the normal function of the resulting protein (loss of function), by causing the resulting protein to have some extra, toxic function (gain of function), or in some cases, both. The recent discovery of the effects on movement in and out of the nucleus has led to a major focus on the gain of function hypothesis. However, some work has indicated that loss of function of C9ORF72 may also be important in ALS and this has still not been well defined. Furthermore, many studies have indicated that there is a reduced amount of C9ORF72 in affected regions, supporting the loss of function hypothesis.
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.
Nothing has been a greater focus of global ALS research over the past few years than C9ORF72 and the majority of the work has emphasized studies centred on gain of function hypotheses. When a mutation causes an extra, toxic function, the first therapeutic strategy is to use advancements in medicine that are capable of reducing the amount of the mutant protein. However, without first understanding whether the normal function of C9ORF72 is crucial to the health of motor neurons and other cell types affected in ALS, such strategies may not be effective, or if mutations cause loss of function, potentially detrimental. This Canadian team is uniquely qualified to comprehensively answer these questions and their findings will ultimately enhance our ability to efficiently target C9ORF72 and its mechanisms in future treatment strategies.