Scientists have discovered that a specific brain cell known as a 'projection neuron' has a central role to play in the brain changes seen in multiple sclerosis (MS). The research, published in Nature, shows that projection neurons are damaged by the body's own immune cells, and that this damage could underpin the brain shrinkage and cognitive changes associated with MS. These new findings provide a platform for specific new MS therapies that target damaged brain cells to be developed.

Multiple sclerosis is a disease of the brain and the spinal cord that affects over two million people worldwide. The potential symptoms of MS are wide ranging and can include problems with vision, movement and cognitive abilities. Previous research has shown that a brain region called the cortex shrinks over time in MS patients, known as cortical atrophy. The processes driving this cortical shrinkage have, until now, been unclear.

In a new international study researchers used post-mortem human brain samples from MS patients to study a wide range of cell types implicated in the disease, and compared their findings to brain samples donated from people that did not have MS.

"Using a new technique called single nuclei RNA sequencing, we were able to study the genetic make-up of individual brain cells to understand why some cells might be more susceptible to damage in MS than others," said the lead scientist.

"Our results showed that a particular type of nerve cell called "projection neurons" were particularly vulnerable to damage in the brains of MS patients."

In healthy people, these projection neurons are involved in communicating information between different areas of the brain. It is therefore possible that the damage to these cells can affect cognitive abilities in MS patients. Moreover, the loss of this particular cell types helps explain why brains of MS patients shrink over time - the more cells that are damaged and lost, the less space the brain takes up.

The authors found signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. 

The researchers also showed that immune cells in the brains of MS patients were targeting projection neurons and causing cell stress and damage.

"We found that antibody-producing immune cells are related to the damage of the important projection neurons in MS brains," said, the senior scientist coordinating the research. "This suggests that cell therapies targeting these immune cells could protect projection neurons and provide a novel treatment for progressive MS."

https://www.nature.com/articles/s41586-019-1404-z