Signaling a new therapeutic target for ALS: Unraveling the role of C9orf72 in synaptic function

In late 2011, a landmark discovery was made which identified that variants in a gene called C9orf72 were responsible for the highest percentage of hereditary ALS and frontotemporal dementia (FTD) cases. Since then, researchers have found that variants in this gene can lead to reduced levels of the C9orf72 protein, but the precise consequences of its loss in the cell remain unclear. Emerging research speculates that C9orf72 plays a critical role in maintaining normal synapses, the place where neurons connect to communicate with each other. C9orf72 deficiency may then lead to synaptic dysfunction – a hallmark of ALS.

Preliminary research suggests that insufficient C9orf72 can affect the structure of synapses, including an increase in the levels of glutamate receptors. Glutamate is a key protein involved in transmitting signals between neurons, but when there is too much glutamate, it can lead to hyperexcitability – an overactivation of brain signals. This hyperexcitability can contribute to motor neuron degeneration and disease progression in ALS.

Additionally, critical pathways that regulate the synaptic function, such as PI3K/Akt are also negatively affected by C9orf72 deficiency. Bryan’s previous research has shown that inhibiting a substance called anaplastic lymphoma kinase (ALK), using a drug called lorlatinib, could correct some of these abnormalities and help restore normal glutamate receptor composition.

In his research, Bryan will investigate further how C9orf72 influences the synaptic function and explore the molecular pathways through which ALK inhibition helps treat synaptic dysfunction. This could lead to significant insights into C9orf72 ALS and promising new therapeutic targets.

Bryan’s supervisor, Dr. Janice Robertson, has focused heavily on the potential contribution of C9orf72 loss of function to ALS and is a leader in the field regarding this hypothesis. Through the ALS Canada Research Program, the lab has been supported multiple times, including with an ALS Canada-Brain Canada Arthur J. Hudson Translation Team Grant in 2016 for $1.65 million.