Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. ALS patients suffer from a progressive loss of motor neurons, leading to respiratory failure within 3 to 5 years after diagnosis. Available therapies only slow down the disease progression moderately or extend the lifespan by a few months. Epigenetic hallmarks have been linked to the disease, creating an avenue for potential therapeutic approaches. Interference with one class of epigenetic enzymes, histone deacetylases, has been shown to affect neurodegeneration in many preclinical models. Consequently, it is crucial to improve our understanding about histone deacetylases and their inhibitors in (pre)clinical models of ALS. We conclude that selective inhibitors with high tolerability and safety and sufficient blood–brain barrier permeability will be needed to interfere with both epigenetic and non‐epigenetic targets of these enzymes. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

“…By using a potent HDAC inhibitor, ACY-738, and by combining transcriptomic and lipidomic analysis, our data demonstrated a link between epigenetic modifications and lipid metabolism defects in the spinal cord of a FUS mouse model of ALS. While these two cellular processes appear to be commonly implicated in ALS pathology and actively participate in disease progression [ 11 , 25 ], our results highlight HDAC inhibition as a relevant potential therapeutic strategy to treat this devastating disease.…”

“…Class III includes SIRT1-7. Class IV is represented only by HDAC11 [ 11 ]. While the activity of some HDACs contributes to disease onset and progression, other isoforms play beneficial roles.…”

“…While the activity of some HDACs contributes to disease onset and progression, other isoforms play beneficial roles. Consequently, the selective modulation of the activity of specific HDAC isoforms has the potential to modify the disease course of ALS [ 11 ]. In this context, we and others provided substantial evidence for the use of selective HDAC inhibitors in ALS [ 6 , 9 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Recent advances in the pathogenesis and therapeutics of amyotrophic lateral sclerosis

“…Ludo Van den Bosch and coworkers reviewed in this Themed Issue, the potential of interfering with histone deacetylases, one class of epigenetic enzymes. They explored the potential of known inhibitors such as valproate, lithium, and resveratrol, along with some novel synthetic inhibitors, for the different histone deacetylase subtypes, including the sirtuins, in preclinical models and a few clinical studies, paying particular attention to their ability to cross the blood–brain barrier and their tolerability and safety (Klingl, Pakravan, & Van Den Bosch, 2020).…”

“…paying particular attention to their ability to cross the blood-brain barrier and their tolerability and safety (Klingl, Pakravan, & Van Den Bosch, 2020).…”