Proteins are essential building blocks the body uses to make tissues such as muscles, cartilage, skin and blood. Conventional science assumes that a section of DNA known as a gene provides instructions for a single protein, or “encodes” a single protein. A molecule called messenger RNA carries those instructions for the production of one specific protein.

A novel discovery

Dr. Xavier Roucou, a cell biologist and biochemical researcher at l’Université de Sherbrooke and his team were some of the first scientists in the world to discover in 2013 that messenger RNAs carry several sets of instructions for making what are called alternative proteins (altProts), in addition to the previously known ones. These altProts are not just variations of the known proteins; they are entirely different. The discovery of this novel set of proteins that can be made in the human body was published in multiple scientific journals and recognized in several scientific prizes for Dr. Roucou’s lab.

For the discovery, Dr. Roucou and his team created an innovative database that predicts all of the places within the human genome that may contain the extra codes for making altProts. By chance, Dr. Marie Brunet, a postdoctoral research fellow working in his lab found that the FUS gene, one of the genes known to cause familial ALS and some cases of sporadic ALS, carries instructions for making altFUS, in addition to the FUS protein. They confirmed their discovery after creating a new antibody designed to identify altFUS. An antibody is a molecule that can recognize a specific protein. For example, when you are sick with the cold virus, your body makes antibodies that recognize specific proteins on the surface of the cold germs so your immune cells can attack them.

“Our preliminary experiments with fruit fly models suggest that altFUS and FUS proteins may cooperate to create toxicity seen in ALS disease processes,” said Dr. Roucou, who is also the Canada Research Chair in Functional Proteomics and Discovery of Novel Proteins. His work to date in lab experiments suggests that altFUS protein may cause toxicity in neurons in three ways: (1) by altering the energy-producing structures called mitochondria; (2) by impairing the neurons ability to clear out waste products in a process known as autophagy; and (3) by encouraging the FUS proteins to aggregate.

A new frontier in ALS research

With a $125,000 grant from the ALS Canada Research Program in 2018, Dr. Roucou and Dr. Brunet will explore how altFUS and FUS proteins participate in ALS disease processes. They will look for differences in altFUS protein in human ALS by comparing post-mortem brain tissue with and without the disease. They will also explore whether mutated altFUS collaborates with FUS protein in ALS progression, or if altFUS alone may be a driver of the disease.

They will also re-analyze data from a data set of cerebrospinal fluid from people with a variety of other conditions to see if the presence of altFUS protein in cerebrospinal fluid of people with ALS could be a promising biomarker or indicator of prognosis.

“If our proof of principle project with altFUS is successful, it will open the door for future research to explore a whole new pool of altProts that could potentially be involved in ALS that we have been missing,” said Dr. Brunet. There is a good reason to believe that a whole previously undetected set of altProts are ready to be investigated: “Of the top 50 genes that are associated with ALS, 75 per cent have an altProt that has been detected at least once in lab experiments”.

There is a lot of passion and collaboration in the ALS research community. Dr. Roucou has posted his OpenProt database online to share his genetic sequencing data for human altProts with other scientists. He and Dr. Brunet are also happy to collaborate with other scientists to share their method for creating the protein-specific antibody tool.

“ALS is very complex, involving different genes and many mutations. We believe investigations of altProts may help us to figure out the mechanisms of the disease,” Dr. Roucou said.

This research project is one of 8 research projects funded in 2018 by the ALS Canada Research Program, which is the only dedicated source of funding for ALS research in Canada. The funding of the project followed a rigorous scientific assessment by panels of global ALS experts. The panellists evaluated a larger pool of applications to identify the projects that demonstrate scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.

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Posted in: Research