Multiple sclerosis (MS) is an autoimmune disorder, in which the immune system attacks an insulating sheath that coats neurons called myelin. Myelin helps to rapidly transmit the electrical impulses that travel through neurons and enable movement. As the myelin sheath sustains damage from the immune attacks, the neurons inside the myelin may also be disrupted. This myelin and nerve damage can cause pain, fatigue, movement difficulties, vision loss, and the body may eventually become unable to maintain basic functions.
MS treatments are primarily aimed at managing symptoms or reducing the rate and intensity of autoimmune attacks. Unfortunately, the nerve damage that occurs cannot be repaired, and the neurodegeneration continues.
Researchers have now learned more about the mechanisms underlying the disease by taking a new approach in analyzing small variations in the human genome that increase the risk of MS. The scientists found that immune cells are not the only kind of cells that are involved in the disease; MS-linked genetic variants were identified that disrupt cells called oligodendrocytes, cells of the brain that provide support and insulation. The findings have been reported in Cell.
“The idea that only genetic variants that affect your immune system are important in MS always struck me as incongruous with the way that the brain is so impacted,” study leader and Whitehead Institute Fellow Olivia Corradin. “Although the disease is primarily autoimmune, it makes sense that some aspect would be intrinsic to the brain.”
Genetic risk factors for MS have already been identified, but Corradin's team wanted to know more about what these variants were doing. They created a method Carrodin dubbed the outside variant approach, which assesses each risk variant in the framework of the three-dimensional structure of the genome in the nucleus. When DNA is compacted, it can place regions of the genome that are far from one another on chromosomes in close physical proximity. They found regulatory regions that are in the same space as MS risk variants, which also target the same gene. If one of those variants was increasing the risk of MS with an outside variant neighbor, more than either on their own, Corradin looked for the cell types where they would be active.
The study confirmed previous findings; immune T and B cells are the types that are primarily affected in MS. However, it also revealed that oligodendrocytes are impacted.
Additional studies showed that the MS-linked genetic variants were interfering with the transcription of genes in immature oligodendrocytes. In some cases, the cellular machinery was paused at the point where it starts to transcribe DNA into RNA. The researchers suggested that this could be preventing oligodendrocytes from maturing, which reduces the amount of myelin that would be used to replace what is lost during an autoimmune attack. These findings may open up new therapeutic avenues for MS, which promote oligodendrocyte maturation and the repair of myelin.
The outside variant method may also be useful for the study of other diseases, and Corradin's lab may be looking at complex diseases like cancer or heart disease next.
“With complex diseases, there is a huge amount of variation among patients, in terms of both genetics and disease progression, and the same treatment is not equally effective for every patient,” said co-first study author and researcher Anna Barbeau. “Our approach can lend insight into developing novel therapeutics that might benefit people who don't respond well to existing treatments.”