A multi-centre team of investigators have identified critical neurons in the grey matter, the “thinking” portion of the brain, that are especially prone to DNA damage as neurological disease-related inflammation progresses.
The findings, stemming from two complementary studies published this week in Nature, could lead to therapies to protect the brain in neurological conditions like multiple sclerosis (MS).
Researchers from University of Cambridge and Cambridge Stem Cell Institute, Cedars-Sinai Guerin Children’s and University of California, San Francisco (UCSF) focused on a group of brain cells called ‘CUX2 neurons’. Located on the outer layer of the brain, known as the cortex, CUX2 neurons are linked to brain communication, movement, thinking and memory. They are also linked to many neurological conditions including MS, autism, epilepsy and Alzheimer’s disease.
In the first study, researchers found that CUX2 neurons are especially sensitive to damage caused by inflammation. In diseases like MS, the body’s immune system attacks the brain, leading to long-term damage. While MS has been thought to primarily affect white matter in the brain, this research shows that it could also damage particularly vulnerable CUX2 neurons in the grey matter.
This damage may help explain why people with MS can experience memory problems and cognitive decline as the disease progresses.
“The CUX2 neurons are like a ‘canary in the coal mine’ for the brain affected by MS,” said David Rowitch, MD, PhD, corresponding author of both studies, and Professor of Paediatrics at the University of Cambridge and Director for Research, Cedars-Sinai Guerin Children’s, and former Group Leader at the Cambridge Stem Cell Institute. “They are early warning signs of trouble. If we can protect these cells, we might be able to contain the damage at an early stage before the disease progresses.”
To better understand the workings of CUX2 neurons, investigators performed genetic sequencing of brain tissue from people with MS, and in laboratory mice that can model MS. Their study concluded that these neurons, when under stress, sustain much more DNA damage than neighboring brain cells do. Over time, this damage can lead to cell death.
Authors Laura Morcom (former CSCI PhD student), Gabriel Balmas, and David Rowitch.
In the second study, investigators found that CUX2 neurons are also vulnerable to DNA damage during development and use the molecule ATF4 to help repair their DNA. ATF4 and the molecules it regulates act like a switch that turns on genes that protect critical brain cells from DNA damage, the study shows.
Even with these repair tools, the study found that CUX2 neurons remain at risk, especially during long-term inflammation. This may be one reason the condition of people with progressive MS continues to worsen even when treatments reduce inflammation.
“We were excited to find that these brain cells already have natural ways to repair themselves,” said Stephen Fancy, PhD, DVM, co-corresponding author of the study and associate professor in the departments of Neurology and Pediatrics at UCSF. “By uncovering how certain brain cells protect and repair themselves, we have taken a significant step toward developing treatments that could one day preserve brain function and quality of life.”
Further research is needed to bring the findings into clinical use, but they represent a step toward new approaches to treating brain diseases—one that focuses on limiting DNA damage, enhancing repair and bolstering the resilience of critical brain cells. Indeed, the study found several factors that can be turned on to prevent damage, which could prove be the way forward in protecting the brain’s most vulnerable cells.
“Although we can successfully treat the early inflammatory phases of multiple sclerosis, we are less able to treat the slow progressive death of nerve cells, which occurs over years, and leads to impaired thinking and mobility in people with the disease,” says Alasdair Coles, Professor of Clinical Neuroimmunology and Head of Clinical Neurosciences at the University of Cambridge. “These two exciting studies help us understand why this nerve death occurs, and how we might prevent it. Firstly, we learn that particular nerve cells in the cortex of the brain, used for higher thinking and movements, are especially vulnerable to dying in the face of inflammation. And, secondly, the reason they die is because they accumulate DNA damage. So, if we can prevent DMA damage in these nerve cells, we might prevent the worse consequences of multiple sclerosis. This is an entirely new treatment approach for multiple sclerosis.”