Cure SMA and Cure SMA Canada have awarded a $150,000 research grant to Jocelyn Cote, PhD, at the University of Ottawa for his project, “Investigating the contributions of CARM1 and HuR misregulation to SMA skeletal muscle and NMJ defects.”

While an essential role for SMN in spinal cord motor neurons remains central to the pathophysiology of SMA, the potential contribution of other organs/tissues to disease process is largely unknown. Dr. Cote and his team wish to explore and increase the growing body of evidence which suggests that intrinsic muscle pathology could have important contributions in the disease, although the mechanisms by which SMN functions in muscle are largely unknown.

Dr. Cote and his team have found that the misregulation of the CARM1/HuR pathway due to loss of SMN contributes to skeletal muscle and NMJ defects observed in SMA. In this grant, they will investigate this regulatory pathway and elucidate its potential contribution to disease processes.

The grant to Dr. Cote is co-funded by Cure SMA Canada.

Meet Dr. Cote

Who are you?

I am a biochemist and molecular biologist by training with specific expertise in the field of post-transcriptional regulation of gene expression. Transcription involves the synthesis of so-called messenger RNA from a DNA template resulting in the transfer of genetic information from the DNA molecule to the messenger RNA. Post-transcriptional mechanisms include the mechanism that allows the messenger RNA to be differentially “spliced”- depending on cell type or environmental conditions- through a process called alternative splicing. Post-transcriptional mechanisms also include the regulation of the transport, localization, and effective life span of the RNA messenger, as well as the specific modifications to the proteins that participate in these processes.

I obtained my PhD from the University of Sherbrooke in the province of Quebec, Canada. I then pursued my training as a postdoctoral fellow at Washington University-St. Louis in the U.S. and at McGill University in Montreal, Qc, Canada.

I started my independent research group at the University of Ottawa in 2004 and I am now a Professor in the Department of Cellular and Molecular Medicine and the Assistant Dean, Research for the Faculty of Medicine.

How did you first become involved with SMA research?

Coming from a biochemical background, I initially started working on SMA because I identified SMN, or more specifically a part of the SMN protein called the Tudor domain, as a domain capable of ‘sensing’ a special protein modification termed ‘arginine methylation’. Following this discovery, we reasoned that these ‘methylated’ proteins might represent a major subset of proteins that would stop functioning normally in the absence of SMN in SMA patients, and that studying these proteins might help us gain a better understanding of what SMN does in spinal cord motor neurons and how loss of its activity leads to SMA. Although it started primarily as a scientific question, after I first attended the Annual FSMA, now Cure SMA, Research Conference back in 2002 and met with SMA kids and their families, it became clear to me that I was going to do my best to contribute my expertise towards increasing our fundamental understanding of this disease in the hope that it would help one day in the elaboration of novel therapeutic strategies.

What is your current role in SMA research?

My lab uses biochemical and cellular biology approaches, working with various models of SMA, in order to gain a better understanding of the precise function that SMN plays in spinal cord motor neuron, and how loss of that function leads to the disease. For example, we are trying to identify the other proteins and RNA molecules that SMN interacts with and controls in motor neurons, with the logic that this should give us some insights into what SMN is doing in this cell type. Then, we assess if these SMN interacting partners could represent valid targets that might be easier to manipulate than SMN itself to improve the SMA phenotype.

What do you hope to learn from this research project?

We have discovered that an important regulatory protein (called CARM1) is abnormally over-expressed in SMA muscles. We propose to study how this protein may contribute to the development of the problems that are observed in SMA muscles and postulate that targeting this protein may represent a novel therapeutic strategy to complement existing approaches restoring SMN mainly in spinal cord motor neurons.

How will this project work?

We propose to use a series of biochemical, molecular and cellular approaches that will allow us to determine what pathways are affected by the abnormal expression of CARM1 in SMA muscles. We want to learn how these pathways impact normal muscle development and connection of the motor neuron with muscles and muscle function. For those experiments we are using various cell culture and mouse models of SMA, but also validating our results using SMA patient cells to ensure that our findings are relevant to the human condition.

What is the significance of your study?

With the availability of a new therapeutic options that focused on SMN restoration, it is very important to fully understand the role of SMN in all tissues, including skeletal muscle, in order to inform the development of more efficient or combinatorial therapeutic approaches. Since most of the current therapies are aimed at improving motor neuron numbers and function, it is also crucial to ensure that motor neurons can form stable, functional connections with skeletal muscle.

Basic Research Funding

This grant to Dr. Cote is part of $1,150,000 in new basic research funding that we’re currently announcing.

Basic research is the first step in our comprehensive research model. We fund basic research to investigate the biology and cause of SMA, in order to identify the most effective strategies for drug discovery. We also use this funding to develop tools that facilitate SMA research.

Past Announcements

$200,000 to Alberto Kornblihtt, PhD

$200,000 to Charlotte Sumner, PhD

$150,000 to Veronica Pessino, PhD

$150,000 to Laxman Gangwani, PhD