New discovery may revolutionize treatment of ALS

Canadians researchers have made a significant discovery regarding ALS (amyotrophic lateral sclerosis), also known as Lou Gehrig’s disease, opening the door to novel approaches to the treatment of the disease.

The discovery is significant because, to date, there is no cure or effective treatment for ALS, a progressive neuromuscular disease caused by deterioration of motor neurons in the brain and spinal cord. Individuals living with the disease experience progressive paralysis, including the muscles involved in breathing and swallowing. Approximately 2,500 to 3,000 Canadians currently live with this fatal disease.

Published in September in a paper called “Intermolecular transmission of SOD-1 misfolding in living cells” in the Proceedings of the National Academy of Sciences (PNAS) by a team of researchers from the University of British Columbia, Vancouver Coastal Health Research Institute and University of Alberta, the research found a key link between prions and ALS.

The study demonstrates that the SOD1 protein (superoxide dismutase 1), which has been shown to be implicated in the ALS disease process, exhibits prion-like properties. The research found that SOD1 participates in a process called template-directed misfolding. This term refers to the coercion of one protein by another protein to change shape and accumulate in large complexes in a fashion similar to the process underlying prion diseases.

Correctly-folded proteins adopt one particular structure in order to carry out their intended function. A protein’s failure to adopt this correct structure is what threatens the health of cells. Prions are “misfolded” proteins – the infectious, aggregating agents in diseases such as Creutzfeldt-Jakob disease (CJD) in humans, chronic wasting disease (CWD) in deer and elk and bovine spongiform encephalopathy (BSE), also known as “mad cow” disease in cattle. In ALS, Alzheimer’s and Parkinson’s disease, the misfolded proteins are SOD1, amyloid-β, and α-synuclein, respectively.

These findings provide a molecular explanation for the progressive spread of ALS through the nervous system, and highlight the central role of the propagation of misfolded proteins in the pathogenesis of neurodegenerative diseases, including ALS, Alzheimer’s and Parkinson’s.

This is the first time this “domino effect” has been discovered in association with ALS. But this process has an Achilles heel. If the process of propagation from cell to cell can be blocked, the progression of ALS might be arrested.

The discovery identifies a specific molecular target, which when manipulated halts the conversion of the SOD1 protein to a misfolded, disease-causing form.  This is a first-step toward the development of targeted treatments that may stop progression of ALS.

“For many years, ALS has remained a complex puzzle. We have found a key piece to help guide the research community to solutions,” says Dr. Leslie Grad, a co-first author of the project and current Manager of Scientific Programs at Vancouver-based PrioNet Canada, one of Canada’s Networks of Centres of Excellence that develops strategies to help solve the food, health safety, and socioeconomic problems associated with prion diseases. “PrioNet is further exploring this discovery through newly-funded research projects.”
The work was completed by a team at the Brain Research Centre based at theUniversity ofBritish Columbia and the Vancouver Coastal Health Research Institute, in collaboration with researchers at theUniversity ofAlberta. The research was supported by PrioNetCanada and in part by Amorfix Life Sciences and the Canadian Institutes of Health Research.

After having achieved international attention for scientific discoveries and risk management strategies directed at controlling prion diseases, PrioNet Canada is now directing capacity into therapeutic solutions for prion-like diseases of aging, such as Alzheimer’s, Parkinson’s and ALS. While each of these diseases manifests itself in a different way, the hallmark of each is a progressive accumulation of misfolded protein aggregates in the central nervous system.

The World Health Organization predicts that neurodegenerative diseases will surpass cancer as the second leading cause of death inCanadaby 2040.

This forecast reinforces the need for further research into neurodegenerative diseases to continue to explore novel approaches and treatments.

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