U of T researchers help reveal key gene-environment interplay in multiple sclerosis

Working with scientists at the University of California, Professors Jim Dennis of molecular genetics and Kathy Siminovitch of medicine have discovered a critical, unifying molecular mechanism underlying the genetic and environmental risk factors for multiple sclerosis (MS)—representing a major step forward in understanding the onset of MS, one they hope will help lead to new, targeted therapies for the debilitating disorder.

The study was published online May 31 in Nature Communications.

MS is a chronic neurodegenerative illness resulting from complex gene-environment interactions. But just how these factors converge to induce the disease has until now remained a puzzle.

“These results are the culmination of 10 years of research examining the interactions of various proteins and sugars at the cell surface, representing a landmark finding of a common molecular pathway in MS,” said Dennis, who is also a senior investigator at Mount Sinai Hospital’s Lunenfeld Research Institute. “We also have evidence for the same pathway playing a role in other autoimmune disorders including Type 1 diabetes.”

The study is the result of a long-term collaboration between Dennis and Dr. Michael Demetriou (senior author) at the University of California. Their earlier Lunenfeld-based work revealed that changes to specific sugars on proteins—a process known as protein glycosylation—promote spontaneous MS-like disease. Follow-up studies showed that the dietary supplement N-acetylglucosamine suppresses this process in mice.
In the current study, DNA samples from approximately 13,000 people in North America with and without MS were analyzed in the Demetriou lab to determine the effect of three previously identified critical gene variants (termed interleukin-7 receptor-alpha, interleukin-2 receptor-alpha, and CTLA-4).

Remarkably, the scientists found that these three molecules interact with key enzymes that control how proteins are decorated with sugar units (i.e., glycosylation). In other words, variants of these genes found in the human population interacted with one another through a common unifying mechanism to determine risk for MS. This mechanism is the control of protein glycosylation in immune cells.

It has long been known that lack of exposure to sunlight and/or low levels of vitamin D3 are risk factors for MS. In the study, vitamin D3 was shown to regulate protein glycosylation and to oppose MS risk factors. A metabolic supplement to the protein glycosylation pathway, N-acetylglucosamine, was also shown to reduce the risk of MS.

“This is a significant step forward in understanding autoimmune diseases and in the development of personalized, more ‘intelligent’ therapies,” said Dennis. He also noted their study opens up new avenues for the treatment of other chronic diseases such as cancer and diabetes, since similar sugar modifications have been implicated in these illnesses.

Dennis’ considerable body of work in protein glycosylation has revealed the importance of protein-carbohydrate modifications in common, complex and chronic illnesses. Carbohydrates alter proteins at the cell surface that control cell growth and the activity of immune and nervous system cells—two critical ‘signatures’ of MS disease processes.

Dennis and Siminovitch received support from the Canadian Institutes of Health Research and the National Multiple Sclerosis Society for this study.