Understanding SMN protein regulation is fundamental to advancing our understanding of SMA and finding new therapies — because a deficiency in the protein leads to the disease.
The grant will allow Côté and his team to build upon their previous work. It has focused on describing a newly discovered role that SMN plays. That role, called translation, involves regulating protein production. The new research could help the team understand how SMN performs translation. It could also help them determine the potential consequences of SMA patients’ loss of this function.
Côté is a biochemist and a molecular biologist with a PhD in RNA metabolism. He started doing SMA research after identifying part of an SMN protein called the Tudor domain, according to a Cure SMA news story. A Tudor domain can sense a specific post-translation — or post-production — modification of proteins called arginine methylation.
The discovery meant the proteins might represent a significant subset of proteins that stopped functioning when SMN was absent in SMA patients, Côté said. Studying these methylated proteins could lead to a better understanding of what SMN does in spinal cord motor neurons and how the loss of these activities leads to SMA, he said.
Côté’s team will use different biochemical, molecular and cellular approaches, as well as disease models, to determine the composition of the regulatory complexes that SMN uses to oversee protein production in motor neurons. The researchers will also try to identify which mRNAs — or molecules that are translated into proteins — are SMN-regulated and whether any are misregulated in the disease.
In addition, the researchers will explore the notion that increasing the activity of factors that regulate activity in SMA cells can compensate for the loss of SMN.
Côté said his expectations for the project are to learn what role SMN plays in regulating protein production, to understand how SMN performs this function, and to learn how its loss in motor neurons contributes to SMA.
Hopefully, the team’s findings will provide key insights into a novel role that SMN plays in spinal cord motor neurons. This means it could help identify novel therapy targets for SMA.