Posted January 20, 2021

Holly Colognato, Ph.D., State University of New York, Stony Brook

Dr. Holly Colognato

The current drugs used in treating multiple sclerosis (MS) decrease the likelihood of myelin damage by modulating the immune system, but they do not promote myelin repair. Therefore, if the myelin has already been damaged or lost, the current therapies available cannot restore myelin, which is needed to restore neuronal function. To design drugs that can overcome this challenge more knowledge about the inner workings of myelin-forming cells is needed. Dr. Colognato has recently discovered that when myelin-forming cells lack a protein called Csk, they upregulate AMPK, a cellular energy sensor complex, and exhibit enhanced myelination. This enhancement of myelin occurs both during normal brain development and during myelin repair in a mouse model of MS in which myelin damage was induced. While little is currently known regarding how energy metabolism in myelin-forming cells impacts their ability to undergo myelin repair, studies to screen existing drugs that are known to influence cellular energy states for potential effects on myelin repair are important. These studies have the potential to impact both relapsing-remitting MS and progressive MS, both of which experience myelin loss that negatively impacts brain function. 

With the support of a Fiscal Year 2017 Exploration - Hypothesis Development Award, Dr. Colognato aimed to understand the inner workings of myelin-forming cells in order to design and produce successful myelin repair therapies. Her team’s study further investigated the effect of Csk loss to determine what cellular signals are altered in Csk-deficient cells and hone in on the cellular signals that enable those cells to become significantly better at myelin repair. They first sought to determine AMPK loss-of-function and activation effects of AMPK on oligodendrocytes and myelin repair in a cuprizone MS mouse model of demyelination. AMPK is a crucial cellular signal that has previously been shown to act as a cellular energy sensor, responding to changing energy levels and influencing cell metabolism. To do this they used an FDA-approved AMPK activator, metformin, and observed that metformin treatment enhanced myelin levels in the corpus callosum. They further pursued the question, can metformin influence oligodendrocytes directly, and, if so, at what stage? They found that, over the short term, metformin can stimulate increases in oligodendrocyte differentiation through mRNA levels of myelin-related genes. Specifically, metformin increased myelin protein mRNA levels at 24 hours, and this further resulted in an increase in the percentage of cells that were positive for a myelin-related protein. Additional metformin treatment resulted in changes in oligodendrocyte morphology and mitochondrial respiration. The investigators observed that low doses of metformin resulted in increased oxygen consumption rates (OCR) while higher doses suppressed OCR. They also observed an increased rate of glycolysis in oligodendrocytes following metformin treatment. These findings have the potential to open further inquiry into the role of energy utilization and production in key oligodendrocyte behaviors including myelination. 

Little is currently known regarding how energy metabolism in myelin-forming cells impacts their ability to undergo myelin repair; however, these findings may lead to future studies to screen other existing drugs that are known to influence cellular energy states for potential effects on myelin repair. Because metformin is already FDA-approved for the treatment of diabetes, future studies may be able to more quickly move to clinical trials for MS patients. The ultimate goal will be to translate these findings into drug discovery to investigate ways to harness these signals to help repair myelin, first in animal models, then in MS patients. 

Link:

Public and Technical Abstracts: Exploration of a Novel Molecular Brake for Remyelination in MS

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