DNA methylation in motor neuron biology and epigeneticopathy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), the 3rd most frequent neurodegenerative disease, is fatal. Skeletal muscles, neuromuscular junctions, and motor neurons in the cerebral cortex, brainstem, and spinal cord that control swallowing, breathing, and movement degenerate, causing paralysis, respiratory arrest, and death. Clinically meaningful disease mechanisms are unknown, and no effective therapies are available. ALS is a polygenic heterogeneous disease seen in 5%-10% of patients as inherited, but most patients have no inheritance pattern. ALS appears to manifest as a complex interplay between many genes in multiple tissues, individual lifestyle, the environment, and metabolism. Monozygotic twin and triplet studies of ALS suggest that epigenetic mechanisms could be involved in the pathogenesis because discordance is seen. Epigenetic anomalies involving DNA and RNA methylation occur in human ALS. Cell and animal models show that motor neuron development and degeneration can be regulated by DNA methylation. This chapter summarizes the DNA and RNA epigenetic anomalies that are prominent in human ALS and models of ALS, concluding with the suggestion that they are promising therapeutic targets with small molecules.