For decades, multiple sclerosis research has focused on myelin, the insulation around the brain's wiring. Scientists paid less attention to another loss that was happening in parallel: neurons in the cortex, the seat of higher thinking and cognition, were quietly dying.
A team led by UC San Francisco, University of Cambridge, and Cedars-Sinai Medical Center now traces that loss to a breakdown in the DNA of neurons as inflammation overwhelms the brain. The finding helps explain why brain scans of people with MS reveal damage not only to white matter, the brain's wiring, but also to the brain's gray matter — and it points to a new direction for the field.
"It's become clear that in addition to promoting remyelination in progressive MS, it's essential to find ways to directly protect grey matter neurons themselves," said Steve Fancy , PhD, DVM, a professor in the UCSF Weill Institute for Neurosciences. He is the co-corresponding author of two papers that appeared April 1 in the same issue of Nature. "We can now point to a mechanism for why these vulnerable neurons in the brain are lost — DNA damage — and begin fighting MS on an entirely new front."
MS is typically diagnosed when clinicians see lesions in the myelin-rich white matter of the brain on MRI scans. White matter is made of the nerves that link brain cells and it looks white on a brain scan.
The brain's grey matter, which houses the "bodies" of the brain cells, can also have MS lesions, especially in its outer layers. These lesions are less common — and harder to see on a brain scan — but they are a sign of chronic and disabling MS.
The scientists wanted to learn more about the neurons that died in these grey-matter lesions, which express a gene called CUX2. In the first study, they looked at developing mouse brains to see how CUX2 neurons are born. This occurs early in life, when the brain is growing quickly, putting cells under tremendous stress.
The cells relied on a mechanism to repair their DNA as they rapidly multiplied, fanned out into the far reaches of the brain and wired up with one another. The mechanism depends on a stress-response gene called ATF4 to keep chromosomes intact. When the team removed ATF4, the growing neurons were rife with DNA damage, and this prevented the frontal part of the brain from forming.
"We saw that just a subset of its neurons were vulnerable to DNA damage," Fancy said. "And ATF4 is at the center of the strategy for surviving it."
In the second study , the team found DNA damage in grey matter lesions from people with MS involving the same neurons.
In mouse models of MS, the researchers saw that inflammation sparked chemical reactions that damaged DNA in CUX2 neurons. The repair systems that protect these neurons from the stresses of development could no longer keep up; and this led to brain damage.
Together, the two studies outline the natural way the brain's outer layer neurons cope with DNA damage — and how that system breaks down in MS.
"The CUX2 neurons are like a 'canary in the coal mine' for the brain affected by MS," said David Rowitch , MD, PhD, deputy director for Research at Guerin Children's, professor of Paediatrics at the University of Cambridge, and co-corresponding author. "If we can protect these neurons, we might be able to contain the damage before the disease progresses."
