Could a Simple Dietary Change Combat "Incurable" Diseases?

Tuesday, October 04, 2016
Karim Mekhail and Joshua Abraham
Professor Karim Mekhail and MD/PhD student Joshua Abraham

Magnesium is essential for health — it plays a role in more than 300 biochemical processes in the human body. But could this mineral, found in many foods and readily available as a dietary supplement, also be a therapy for people with or at risk for neurodegenerative diseases and cancers?

Maybe.

Professor Karim Mekhail holds the Canada Research Chair in Spatial Genome Organization at the University of Toronto's Department of Laboratory Medicine and Pathobiology. In 2014, Mekhail and his lab discovered a completely new function for the yeast version of a human protein called ATXN2. (Mutations in the human ATAXN2 gene cause or promote several incurable and fatal neurodegenerative disorders, including amyotrophic lateral sclerosis or ALS, and spinocerebellar ataxia type 2.)

Mekhail's team found that the ATXN2 protein is essential in the healthy aging of cells because it prevents the accumulation of abnormal, DNA-damaging, nucleic acid structures called RNA-DNA hybrids, or R-loops. And they found that a drastic reduction of sugar calories, termed calorie restriction, could prevent the buildup of toxic hybrids in yeast cells lacking the ATXN2 gene.

Now, Mekhail and his team have made another surprising discovery: those beneficial effects of calorie restriction depend on small increases in the levels of magnesium inside cells. They also showed that simply adding a small amount of magnesium without reducing calories protects cells from the DNA damage and premature aging that often follows loss of the ATXN2 gene and accumulation of RNA-DNA hybrids.

"To our great pleasure, we found that just adding magnesium was quite effective at suppressing hybrids. It wasn't perfect, but we saw 50 to 70 per cent of the effect of calorie restriction," says Mekhail. "We think these results point to a potentially simple intervention such as a measured magnesium supplementation or drug-based modulation of the magnesium-dependent pathway that limits hybrid accumulation in ALS, ataxia, cancer, and possibly other diseases."

The journal Nucleic Acids Research published the findings last month.

Based on their discoveries in yeast and human systems, a major priority for Mekhail’s lab was to determine if the human ATXN2 gene has the same limiting effect on RNA-DNA hybrids in human cells.

MD/PhD student Joshua Abraham and technician Janet Chan led the team's efforts to translate their results from yeast to human cells. "Yeast and humans are evolutionarily separated by over a billion years," says Abraham. "Using gold-standard assays and the latest gene-editing technology, we were able to show the function of the ATXN2 gene is conserved across that remarkable time span."

The researchers next made a list of things in common between two enzymes that appeared critical to the ability of calorie restriction to control R-loops. After eliminating several candidates, they homed in on magnesium.

They also found that magnesium supplementation counters genome-destabilizing hybrid accumulation in human cells deficient in the BRCA2 gene, which is commonly mutated in breast and ovarian cancers.

Mekhail's lab and other researchers have developed methods to accurately measure RNA-DNA hybrid structures in human cells, and those methods continue to improve. "It's an exciting time to be part of this field," says Abraham. "We hope that as our knowledge improves, our investment of time and effort in new techniques will pay further dividends for studies investigating the role RNA-DNA hybrids in several diseases."

Meanwhile, Mekhail takes daily supplements of magnesium, which he says studies show is often inadequate in the Western diet. (Foods with high levels of magnesium include seeds, nuts, legumes, fish and whole grains.)

While Mekhail is excited about the clinical potential of magnesium, he says the study also reaffirms the value of yeast as a model system for basic science. "The speed at which we can go with yeast — in the level of intervention, our ability to poke the biology — put it light years ahead of many systems," he says. "It's a phenomenal model to predict complex molecular biology mechanisms in humans."

Mekhail and members of his team have begun an early-stage collaboration with the university's Innovations & Partnerships Office and MaRS Innovation to commercialize their work on the magnesium-dependent pathway and move it toward experiments in more complex animal models of ALS, ataxia, and cancer. — Jim Oldfield