Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease

Abstract

Amyotrophic lateral sclerosis (ALS) is the third most common adult onset neurodegenerative disorder worldwide. It is generally characterized by progressive paralysis starting at the limbs ultimately leading to death caused by respiratory failure. There is no cure and current treatments fail to slow the progression of the disease. As such, new treatment options are desperately needed. Epigenetic targets are an attractive possibility because they are reversible. Epigenetics refers to heritable changes in gene expression unrelated to changes in DNA sequence. Three main epigenetic mechanisms include the methylation of DNA, microRNAs and the post-translational modification of histone proteins. Histone modifications occur in many amino acid residues and include phosphorylation, acetylation, methylation as well as other chemical moieties. Recent evidence points to a possible role for epigenetic mechanisms in the etiology of ALS. Here, we review recent advances linking ALS and epigenetics, with a strong focus on histone modifications. Both local and global changes in histone modification profiles are associated with ALS drawing attention to potential targets for future diagnostic and treatment approaches.

Keywords: 3′-UTR; 3′-untranslated region; ALS; AMPA; C9orf72; DRE; FTD; FUS; HAT; HCP; HDAC; NFL; PRMT; PTM; RISC; RNA-induced silencing complex; SIRT; SMN; SOD1; SUV39H; TAR DNA-binding protein 43; TDP-43; amyotrophic lateral sclerosis; chromosome 9 open reading frame 72; dipeptide repeat expansion; frontotemporal dementia; fused In sarcoma; high-CpG-density promoter; histone acetyltransferase; histone deacetylase; low-molecular weight neurofilament; miRNA; microRNA; post-translational modification; protein arginine N-methyltransferase; sirtuin; superoxide dismutase 1; suppressor of variegation 3-9 homologue 1; survival of motor neuron; α-amino-3-hydroxy-5-methyl-4-isoxazole propionic Acid.

Figure 1.

Histone Post-Translational Modifications Linked to Different Proteinopathies and Genes in Amyotropic Lateral Sclerosis. Arrows denote an increase or a decrease for a given modification in the context of ALS.