(May 31, 2011—Toronto, ON) Working with scientists at the University of California (Irvine), the Lunenfeld’s Drs. Jim Dennis and Kathy Siminovitch 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 and a finding that they hope will help lead to new, targeted therapies for the debilitating disorder.
The study was published online today 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 Dr. Jim Dennis, Senior Investigator at the Lunenfeld and a Professor at the University of Toronto. “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 Dr. Dennis and Dr. Michael Demetriou (senior author) at the University of California, Irvine. 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 Dr. 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.
Dr. 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.
Drs. Dennis and Siminovitch received support from the Canadian Institutes of Health Research and the National Multiple Sclerosis Society for this study.
MS is a chronic, autoimmune and neurodegenerative disorder that attacks the protective sheath surrounding neurons (cells of the nervous system) in the brain and spinal cord. Symptoms of MS are unpredictable, episodic and vary greatly among people with the illness. Canada has one of the highest rates of MS worldwide.