Hypermethylation May Be Neuroprotective in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

A research team at Penn Medicine recently found that hypermethylation is able to inhibit the development of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration (FTD) in a study titled, “C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence.” The results are published in the journal Neurology.

“This is the first epigenetic modification of a gene that seems to be protective against neuronal disease,” said 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 in a recent news release.

Studies have suggested that expansions of the gene C9orf72 are linked to the TDP-43 TAR DNA binding protein, which is related to both ALS and FTD. “Understanding the role of C9orf72 has the possibility to be truly translational and improve the lives of patients suffering from these devastating diseases,” said senior author, Edward Lee, MD, PhD, assistant professor of Neuropathology in Pathology and Laboratory Medicine at Penn.

A total of 20 patients carrying a mutation in the C9orf72 gene and with a diagnosis of FTD or ALS took part in the research. All participants were evaluated with a blood test to evaluate C9orf72 methylation levels, neuropsychological tests and neuroimaging assessments. Researchers also involved in the study a total of 25 healthy controls.

Results from the MRI showed a reduction in grey matter in many brain areas in the patient groups compared to the controls. Those patients that had hypermethylation of C9orf72 were found to have in the hippocampus thalamus and frontal cortex, more grey matter volume in areas that are affected in ALS and FTD. In order to validate the results the researchers evaluated autopsies of 35 patiets that had C9orf72 expansions and observed that an increased methylation was related with less neuronal loss in the hippocampus and the frontal cortex.

To examine the neuroprotective effects of hypermethylation, the researchers conducted a longitudinal analysis in a total of 11 of the study patients and found a that there is a reduction in the changes of hippocampal grey matter, fontal cortex and thalamus related to hypermethlation. This implies that in patients with C9orf72 hypermethylation, the disease progresses slower. The researchers also found a relationship between hypermethylation and predicted memory decline.

Findings from this study corroborate results from other studies indicating hypermethylation of C9orf72 as a neuroprotective agent. “We believe that this work provides additional data supporting the notion that C9orf72 methylation is neuroprotective and therefore opens up the exciting possibility of a new avenue for precision medicine treatments and targets for drug development in neurodegenerative disease,” said McMillan.