Penn Medicine researchers have discovered that the development of diseases like Amyotrophic Lateral Sclerosis (ALS) and Fronto-temporal Degeneration (FTD) is probably inhibited by hypermethylation, or the epigenetic ability to turn off a bad gene implicated in 10 to 30 percent of patients with these neurodegenerative conditions.
“This is the first epigenetic modification of a gene that seems to be protective against neuronal disease,” says lead author Corey McMillan, PhD, research assistant professor of Neurology in the Frontotemporal Degeneration Center in the Perelman School of Medicine at the University of Pennsylvania.
Expansions in the offending gene, C9orf72, have been seen as a root cause for ALS and FTD. “Therefore, understanding its role is being seen as a breakthrough that could result in improving the lives of patients suffering from these devastating diseases,” says senior author, Edward Lee, MD, PhD, assistant professor of Neuropathology in Pathology and Laboratory Medicine at Penn.
The study included 20 patients who tested positive for a mutation in the C9orf72 gene and were clinically diagnosed with FTD or ALS. These patients were put through a neuroimaging study aimed at assessing the levels of C9orf72 methylation. They also went through a brief neuropsychological screening assessment. The study also featured 25 healthy people with no history of neurological or psychiatric disease (controls).
There was a reduction in grey matter in several areas of the brain of the patients as compared to the controls, MRI scans revealed. Grey matter is vital for the proper functioning of region in the brain which control muscle control, memory, emotions, speech and decision-making. The scans showed more dense grey matter in the hippocampus, frontal cortex, and thalamus, regions of the brain in patients with hypermethylation of C9orf72. These areas are key for the tasks described tasks thereby suggesting that hypermethylation is neuroprotective in these regions.
To validate these findings, the Penn team also looked at autopsies of 35 patients with C9orf72 expansions and found that their pathology also suggested that increased methylation was associated with reduced neuronal loss in both the frontal cortex and hippocampus.
These findings are in line with an increasing number of studies suggesting that hypermethylation of C9orf72 has a neuroprotective effects and opens up an exciting possibility for the development of precision medicine treatments and targets for drug development in neurodegenerative disease.