Blocking a death receptor causes damaged myelin, the protective coating surrounding nerve cells, to repair itself, according to a study published Sunday (July 3) in Nature Medicine. The finding suggests that drugs targeting the receptor could help treat multiple sclerosis by reversing the myelin damage characteristic of the disease.
“Showing remyelination, as they do in vivo and in vitro, is a pretty cool result,” said Richard Ransohoff, a Cleveland Clinic neuroscientist who was not involved in the work. The new receptor is a novel first step in potentially repairing damaged nerves of multiple sclerosis patients, he said.
Current multiple sclerosis drugs slow the disease’s progression by quieting the inflammatory response of the immune system, which attacks the myelin surrounding nerve cells and kills oligodendrocytes, brain cells that make and repair myelin. Without their myelin, nerve cells gradually lose their ability to send electrical signals. But because they suppress the immune response, these drugs make patients more susceptible to rare infections such as viral brain inflammation and diseases such as leukemia.
They also cannot undo existing damage, leading scientists to seek out approaches that stimulate the growth of new myelin or the restoration of existing myelin. Though research has identified several candidate molecules that promote myelin survival, none have yet proven to do so successfully in patients.
Sha Mi, a cell biologist at the Biogen Idec, a Boston biotech company, and her colleagues were studying a multiple sclerosis drug candidate that promotes oligodendrocyte survival when they discovered that a molecule called the death receptor 6 (DR6) kills the brain cells. In 2009, the same receptor was implicated in neuronal cell death in Alzheimer’s disease, binding a precursor to the amyloid beta protein and initiating a cascade that triggers neurons to self-destruct.
To determine whether inhibiting the receptor could fuel new cell growth, the researchers first used a detergent to destroy the myelin sheaths in rat neurons, then blocked the DR6 receptor with an antibody. Sure enough, the treatment kept oligodendrocytes alive and spurred their growth and maturation, which in turn repaired the damaged myelin sheaths, Mi said.
Targeting DR6 also seemed to quiet an overactive immune response. In rats with experimental autoimmune encephalitis (EAE), an inflammatory disease used to model multiple sclerosis, inhibiting the receptor resulted in a noticeable improvement of the rats’ symptoms. “If we are blocking DR6, we can potentially block inflammation as well as blocking cell death,” Mi said.
The findings suggest that targeting DR6 could eventually lead to new multiple sclerosis drugs that repair damaged myelin. But the anti-inflammatory effects of blocking the receptor could be a double-edged sword, because as with the current MS drugs, suppressing the immune system can have unintended consequences, said neuroscientist Bruce Trapp of the Cleveland Clinic, who did not participate in the research. “The market is filled with anti inflammatory drugs that are doing a good job,” he said. “But you cannot get too aggressive because you get very serious side effects.”
S. Mi, et. al, "Death receptor 6 negatively regulates oligodendrocyte survival, maturation, and myelination," Nature Medicine, doi:10.1038/nm.2373, 2001.