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A revelation in protein folding offers hope for potential ALS medicines

Research suggests repurposing an existing chemotherapy drug could slow or stop the deadly neurodegenerative disease.

  • June 20, 2024
  • By Gillian Rutherford

A Canadian team has uncovered a potential cause of amyotrophic lateral sclerosis (ALS) in some patients and has identified a chemotherapy drug that could be repurposed to treat the disease.

Every year, about 1,000 Canadians die of ALS and a similar number are diagnosed. A neurodegenerative disease sometimes called Lou Gehrig’s disease after the famous baseball player whose career and life were shortened by it, ALS causes progressive paralysis of the muscles of the limbs, speech, swallowing and breathing, and usually leads to death within five years.

In research published in the Journal of Biological Chemistry, the team reports on a mechanism behind the misfolding of two key proteins that scientists know are involved in ALS: SOD1 and TDP-43. They identify an amino acid called tryptophan-172 in TDP-43 as a potential trigger that makes the protein SOD1 more prone to misfolding. When proteins misfold, they can aggregate or clump inside cells and interfere with the cells’ function. 

The team introduced antibodies to block or hide the tryptophan-172 on TDP-43 from SOD1, to test whether it is needed to cause misfolding of SOD1 in human cell cultures. The result? The human cell cultures showed no clumping of SOD1 proteins.

Since this is not yet a feasible treatment for humans, the researchers then looked to target SOD1 directly. Based on their previous work and colleagues’ computer modelling to identify drugs that interact with SOD1, they tested a chemotherapy drug called 5-fluorouridine that could be repurposed to interact with the SOD1 protein and prevent misfolding. This drug was tested in zebrafish that have the same proteins, and the team found that the fishes’ motor neuron function improved with the addition of 5-fluorouridine.

“Our research question was, ‘Why are these two proteins misfolding and are they related in some way in causing the disease?’” explains one of the study’s primary authors, Michele DuVal, a fourth-year neurology resident at the University of Alberta. DuVal received her PhD in the lab of biological sciences professor and co-author Ted Allison before undertaking her MD.

“We found that if we were able to stabilize the tryptophans and make the proteins less prone to misfolding, the fish were healthier.”

Identifying candidates from existing approved drugs is an attempt to optimize time and resources while hopefully coming up with a drug that will be able to treat ALS.

Michele DuVal

Michele DuVal
(Photo: Supplied)

Protein misfolding is a common characteristic of ALS and is also seen in other neurological diseases such as Parkinson’s, Alzheimer’s and other types of dementia. Tryptophan is an amino acid we get from our food that is needed for normal growth and function of cells.

The research shows a new way the two proteins involved in ALS interact to cause the disease, revealing a potential target for an intervention using an existing drug.

The research team brought together experts from Alberta, B.C., Quebec and the Netherlands to work on the project, led by Allison and Neil Cashman, a neurology professor from the University of British Columbia.

DuVal says it’s a positive step to identify a drug candidate that has already been approved for use in humans, but further research in cell cultures and animals is necessary to test how 5-fluorouridine might help ALS patients.

“We would be looking for functional outcomes, like how well the fish swim, how well the mice walk and do motor tasks, also how long they live,” she explains. “This is a small piece of what is ultimately a very large drug development pipeline, but identifying candidates from existing approved drugs is an attempt to optimize time and resources while hopefully coming up with a drug that will be able to treat ALS.”

DuVal adds that the ALS research community in Canada works closely together and has made a lot of progress since the Ice Bucket Challenge in 2014, which raised $20 million for research in Canada. In particular, she notes research by Sanjay Kalra at the U of A and Michael Strong at the University of Western Ontario.

“It remains a devastating disease, but in terms of knowledge-building and clinical trial activity we’re doing more than we ever have, and I think it’s a critical time to keep the momentum going and to build that hope.”

The research was funded by the Canadian Institutes of Health Research, Alberta Innovates, the ALS Society of Canada and the Brain Canada Foundation. Ted Allison is a member of the Neuroscience and Mental Health Institute.