Western News – Researchers Tackle Disease Molecules

Groundbreaking genetic discovery made by researchers at the Schulich School of Medicine & Dentistry reveals new clues as to why some people suffer from early onset neurodegenerative diseases.

A recent to study led by the O’Donoghue lab focused on the errors that occur when translating gene products into proteins, allowing researchers to better understand the genetic factors that affect the disease.

Patrick O’Donoghue, holder of the Canada Research Chair in Chemical Biology, and his team examined mutations in transfer RNAs (tRNAs), molecules essential for reading the genetic planes that form the building blocks of key proteins in the body.

In a major leap forward for the field of research, the lab has found in a previous study that the average human is born with 60 to 80 tRNA variants in their genetic makeup – previously, scientists around the world believed that there were only one or two tRNA mutations in humans.

When mutations or variants are present in tRNAs, the blueprints are misinterpreted, which triggers errors in the production of proteins in cells. These errors, or translation errors, show links to the disease.

“If we can understand the molecular mechanisms behind a disease, we pave the way for finding treatments to lessen the damage or completely prevent debilitating diseases,” said Jeremy Lant, a doctoral student who was responsible for most of the experimental work at the project. “Our ultimate goal is to generate clinical impact for real people. “

Supporting translational research from the lab to the bedside is a goal of the new strategic plan.

Research now has the potential to shed light on the genetic causes of several neurodegenerative diseases such as Parkinson’s disease and ALS, and to better determine the factors that influence the age of onset and severity of diseases such as the disease. of Huntington.

The findings could also provide insight into the causes of other life-threatening diseases like cancer.

“We are just starting to decipher how poorly translated tRNAs contribute to human disease,” said Martin Duennwald, project co-investigator and Huntington’s disease model expert. “To move forward, we must develop new research tools to elucidate the mechanisms of tRNA mutants on protein aggregation in disease.”

To discover the dozens of previously unknown tRNA variants, the O’Donoghue laboratory previously collaborated with other Western research groups to sequence the genes of 610 tRNAs in the genomes of 80 individuals.

In the new study, the team looked at particular tRNA mutations, examining how the variants might affect the progression of Huntington’s disease, a neurodegenerative disease characterized by the breakdown of nerve cells in the brain. It causes movement difficulties, speech disorders and psychiatric disorders.

Although Huntington’s disease has identifiable genetic causes, there is no known predictor for the early onset or severity of the disease.

In a healthy body, cells maintain an efficient balance between making protein and breaking it down. But when cells affected by Huntington’s disease have the specific tRNA variant that O’Donoghue’s team is studying, those cells become slower to shed unnecessary proteins.

This lag time results in the formation of large groups of proteins causing disease that cannot be broken down.

For people who are genetically at risk for Huntington’s disease, the tRNA variant may change the age of onset or indicate more serious disease.

The specific variant is found in about two percent of the general population and could affect over 100 million people worldwide.

The team also found that cells with a certain variant of tRNA were resistant to the integrated stress response inhibitor (ISRIB), a compound that may minimize the harmful effects of neurodegenerative diseases – a finding that has implications for treatment protocols for patients.

The major discoveries made by the O’Donoghue lab could be transposed into countless other scientific and medical fields, with the potential to have a huge impact on patient care in the area of ​​neurodegeneration.

“This knowledge will enable clinicians to research specific treatment options for patients with tRNA variants and neurodegenerative diseases,” said O’Donoghue.

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