Hypermethylation of C9orf72 Gene May Be Neuroprotective

C9orf72 hypermethylation helps protect the brain against damage in ALS and frontotemporal degeneration.

Hypermethylation of the C9orf72 gene protects the brain against the progression of frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS), according to a study published in Neurology.

Expansions in the C9orf72 gene have previously been linked to the TAR DNA binding protein (TDP-43) that causes both ALS and FTD. The researchers hoped to discover C9orf72’s role in these diseases in order to better understand them.

The study included 20 patients diagnosed with FTD or ALS who also tested positive for a mutation in the C9orf72 gene. The researchers also included 25 healthy control participants who had no history of neurological or psychiatric conditions. Each participant underwent neuroimaging, a blood test evaluation of C9orf72 methylation levels, and a neuropsychological screening.

Patients with FTD or ALS had reduced levels of grey matter in several areas compared with controls. However, the researchers found that participants who had higher levels of C9orf72 methylation had more dense grey matter in many of the areas affected by FTD and ALS, including the hippocampus, thalamus, and frontal cortex. These findings suggested that hypermethylation helped protect these brain regions from damage.

In order to confirm their findings, the researchers then analyzed the autopsies of 35 people with C9orf72 expansions. The analysis suggested that hypermethylation reduced damage in the frontal cortex and hippocampus, consistent with study results.

The researchers also performed longitudinal analyses on 11 of the patients to see how hypermethylation helped protect the brain over the course of their diseases. These participants had reduced changes in the grey matter of the hippocampus, thalamus, and front cortex, which suggests that hypermethylation slows disease progress of FTD and ALS.

“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 Corey McMillan, PhD, of the Perelman School of Medicine at the University of Pennsylvania.

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