Scientists report that they have uncovered a series of epigenetic modifications in patients with amyotrophic lateral sclerosis (ALS) that could have therapeutic implications. The massive research team involving 76 investigators from 16 countries published its study “Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS” in Science Translational Medicine.
ALS is a fatal neurodegenerative disease affecting some 18,000 individuals in the United States with no known cure. The various causes are not completely understood but the disease has an estimated heritability of around 50%, indicating that ALS onset can arise from both genetic and environmental/lifestyle risk factors.
Although epigenetic risk factors have been studied in small patient samples, until now there has not been a large genome-wide analysis of DNA methylation patterns in ALS measured against patient survival, leading to conflicting results and only a few established factors. Therefore, researchers around the world have been compiling their results of genome-wide analysis studies (GWAS) in order to identify different epigenetic patterns to provide insight into ALS etiology and disease processes. They then conducted a large DNA methylation study to identify differentially methylated positions (DMPs) on 42 genes related to epigenetic factors, such as metabolism, cholesterol biosynthesis, and immunity.
The research team found that the genes annotated to the DMPs were enriched for pathways related to cholesterol biosynthesis. Genes DHCR24, ABCG1, MSM01, and SLC7A11 had above average DNA methylation patterns that correlated to HDL and total cholesterol, as well as BMI-related traits (diabetes and hepatic fat content). Moreover, SLC7A11, which had been previously associated with alcohol intake, proved to be an epigenetic risk factor for ALS.
“The association found in SLC7A11—and by extension alcohol as a risk factor for ALS—is related to two well-established pathologic processes in ALS; glutamate excitotoxicity and/or oxidative stress,” the scientists wrote.
Subsequently, genome analysis indicative of the connection between ALS risk and blood cholesterol could also be indicative of raised cholesterol levels in the spinal cord and the brain.
The team also found that an altered metabolism can play a part as an epigenetic factor in ALS onset. They noted that “lowered BMI throughout the course of the disease, as well as various other systemic metabolic alterations, including hyper-metabolism and hyperlipidemia, have been reported in patients with ALS… metabolism may be altered because of mitochondrial defects, uncontrolled fasciculations, or increased respiratory effort.”
According to the researchers, these disrupted pathways “may be a potential avenue for therapeutic intervention, because diet represents a modifiable factor… [and] could benefit disease prognosis, by compensating for defects in lipid metabolism or compensating for the increased energy demand of lower BMI.”
The new study also includes data on the immune system and its role in ALS. Genes were enriched in immune-related traits such as IgE, asthma, and allergic sensitization. These enrichments are associated with altered white blood cell proportions, specifically a higher ratio of granulocytes and a lower ratio of lymphocytes in ALS patients. The researchers say that “an increase in granulocyte proportions is associated with worse prognosis… contributing to neuroinflammation.”
These findings are promising for potential therapeutic intervention, as white blood cell activity is able to be altered pharmaceutically. Team members, who concluded that their findings “could be of interest for new treatments, especially given that mast cell activity can be influenced therapeutically,” came from academic or medical institutions based in Australia, Belgium, Brazil, Canada, France, Ireland, Israel, Italy, Malta, Netherlands, Portugal, Spain, Switzerland, Turkey, United Kingdom, and the United States.