Why some brain cells are particularly vulnerable to multiple sclerosis

Brain cells that help make us human are also uniquely vulnerable to multiple sclerosis.

A newfound cellular repair kit can’t keep up with the disease’s damage, leading to the cell death that’s a hallmark of progressive MS, researchers report April 1 in two papers in Nature.

The discovery uncovers an important and underexplored mechanism behind how the condition progressively shrinks the brain. By better understanding how MS kills brain cells, scientists can design treatments aimed at preventing cognitive decline, says David Rowitch, a developmental neuroscientist at the University of Cambridge.

Each year, 10,000 people in the United States are diagnosed with MS. The body’s immune system attacks neurons in the brain, causing inflammation and unpredictable flare-ups of muscle weakness, tingling and pain. Research has primarily focused on the way the disease causes nerve fibers to lose myelin, the fatty insulation that helps them send messages. But in a second, progressive phase, neurons in the brain begin to die. Patients experience sharper declines in their cognitive ability, leading to difficulties in memory and reasoning as their brains shrink.

“There’s no treatment really for that part,” says Steve Fancy, a neuroscientist at the University of California, San Francisco.

Previous research identified a specific group of neurons in the human cortex, the brain’s wrinkly outermost layer, that are particularly vulnerable to degeneration in progressive MS. Called CUX2 neurons, these brain cells help make up two layers of the cortex thought to play an important role in things like cognition and computation. These layers in the brain are “really very important for making us human,” Fancy says.

CUX2 cells multiply rapidly as the brain develops, but that fast pace comes at a cost, Fancy says. These cells also have a higher risk of accruing DNA damage.

In the first paper, the team identified a DNA repair kit crucial for the initial survival of CUX2 cells. The cells use a protein called ATF4 to jump-start the DNA repair response and prevent damage as the neurons develop. When the researchers switched off ATF4 in mice, CUX2 neurons in their brains quickly died.

Next, the researchers found evidence that DNA damage is the primary culprit behind the degradation of CUX2 cells. In brain tissue from humans with MS, the layers CUX2 neurons reside in showed significantly higher DNA damage compared with those in healthy brains. The team also looked at mice engineered to develop an MS-like condition and found that CUX2 cells died from DNA damage.

The researchers think the DNA damage that these cells face early on in development could leave them more vulnerable later in life. Then, the havoc wreaked by inflammation from MS is simply too much. “We see this kind of consistent theme that these cells just don’t handle this extra stress very well,” Rowitch says.

He also says that while most research in the field has focused on developing therapies to restore myelin to nerve fibers, the discovery points to a new place to direct future treatments.

Don Mahad, a neurologist at the University of Edinburgh who was not involved in the research, agrees. “This tells us that actually, we can’t ignore these intrinsic vulnerabilities of the nerve cell, and that has to be a treatment target,” he says. Current treatments for MS focus on tamping down inflammation caused by the body’s immune system.

“It’s the beginning of a long journey,” Mahad says, “but it’s an important beginning.”