Epigenetic Mechanisms of Gene Regulation in Amyotrophic Lateral Sclerosis

Abstract

Despite being clinically described 150 years ago, the mechanisms underlying amyotrophic lateral sclerosis (ALS) pathogenesis have not yet been fully understood. Studies in both animal models of ALS and human patients reveal a plethora of alterations such as increased glutamate-mediated excitotoxicity, redox stress, increased apoptosis, defective axonal transport, protein-misfolding events, mitochondrial impairment and sustained unregulated immune responses. Regardless of being sporadic or familiar ALS, the final outcome at the cellular level is the death of upper and lower motor neurons, and once diagnosed, ALS is typically lethal within the next 5 years. There are neither clear biomarkers nor therapeutic or disease-modifying treatments for ALS.Accumulating evidence supports the concept that epigenetic-driven modifications, including altered chromatin remodelling events, RNA editing and non-coding RNA molecules, might shed light into the pathogenic mechanisms underlying sporadic/familiar ALS onset and/or severity to facilitate the identification of effective therapies, early diagnosis and potentially early-stage therapeutic interventions to increase the survival outcome of ALS patients.

Minimotifs dysfunction is pervasive in neurodegenerative disorders

“…Minimotifs are the foundation of the histone code. Enzymes that covalently modify minimotifs, including those in histones, are central to AD, PD, ALS, HD, and other polyQ track expansion disorders summarized in recent reviews [258][259][260][261][262][263].…”

Liquid biopsy: a new source of candidate biomarkers in amyotrophic lateral sclerosis

“…The etiology of ALS remains unknown though it has been suggested that interaction between a genetic susceptibility profile and certain environmental factors may contribute to the disease through epigenetic changes . In fact, some studies have shown that ALS patients harbor specific epigenetic marks as changes in DNA methylation in the central nervous system (CNS) .…”

Class I and II histone deacetylase expression is not altered in human amyotrophic lateral sclerosis: Neuropathological and positron emission tomography molecular neuroimaging evidence

“…Specifically, alterations in gene expression in postmortem human samples have led to the hypothesis that correcting epigenetic abnormalities may alter pathogenesis. Moreover, class I and class II histone deacetylases (HDACs) were reported to be altered in postmortem motor cortex and spinal cord as well as in in vitro and in vivo models of ALS . However, there is a clear discord in previous reports focused on HDACs and their downstream targets in ALS.…”

“…Previous studies have provided evidence for epigenetic dysregulation in ALS. Specifically, alterations in gene expression in postmortem human samples [5][6][7] have led to the hypothesis that correcting epigenetic abnormalities may alter pathogenesis. Moreover, class I and class II histone deacetylases (HDACs) were reported to be altered in postmortem motor cortex and spinal cord as well as in in vitro and in vivo models of ALS.…”

“…Moreover, class I and class II histone deacetylases (HDACs) were reported to be altered in postmortem motor cortex and spinal cord as well as in in vitro and in vivo models of ALS. [5][6][7][8] However, there is a clear discord in previous reports focused on HDACs and their downstream targets in ALS. Specifically, there are contradictory reports in the literature centered around the expression of specific HDAC proteins and messenger RNA (mRNA) in ALS as well as the acetylation status of downstream targets.…”