Class-IIa Histone Deacetylase Inhibition Promotes the Growth of Neural Processes and Protects Them Against Neurotoxic Insult

Abstract

Small molecule histone deacetylase inhibitors (HDIs) hold much promise as pharmacological modifiers of the epigenetic status of the central nervous system (CNS), given their ability to cross the blood-brain barrier. This is particularly relevant given the lack of disease-modifying therapies for many neurodegenerative diseases and that epigenetic perturbations are increasingly recognised as playing a key role in their pathophysiology. In particular, emerging evidence in recent years has shown that epigenetic dysregulation may contribute to dopaminergic neuronal death in Parkinson's disease. As a result, a number of pan-HDIs have been explored as potential neuroprotective agents for dopaminergic neurons. However, it is not known if the neuroprotective effects of pan-histone deacetylase (HDAC) inhibition are a general phenomenon or if these effects require inhibition of specific classes of HDACs. Here, we examine the ability of class-specific HDIs to promote neurite growth in a variety of cellular contexts. We find that MC1568, a class IIa-specific HDI, promotes neurite growth and arbourisation and protects neurite arbours against neurotoxic insult. Furthermore, we show that class IIa-specific HDAC inhibition results in activation of the canonical Smad signalling pathway, which is known to promote the survival and growth of midbrain dopaminergic neurons. These results demonstrate the potential of class IIa-specific HDIs as regulators of neuronal structure and suggest they should be examined in animal models of Parkinson's disease as the next stage in rationalising their use as a potential therapy for this disorder.

A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

“…cells and other cellular models of midbrain DA neurons in vitro (Chen et al 2006;Chen et al 2007;Collins et al 2015;Gardian et al 2004;Kidd and Schneider 2010;Kidd and Schneider 2011;Kontopoulos et al 2006;Outeiro et al 2007;St Laurent et al 2013;Wu et al 2008;Zhu et al 2014). However, to our knowledge, the present study is the first to show that a selective HAT activator can induce similar neurotrophic effects in the SH-SY5Y neuronal cell line.…”

“…While HDAC inhibitors have previously been shown to induce neurite growth in these cells (Collins et al 2015;Yuan et al 2001), this is the first report documenting the ability of a HAT activator to promote SH-SY5Y neurite growth. This is an important finding considering the limited number of HAT activators which have been produced (Schneider et al 2013), and the corresponding paucity of studies investigating their neurotrophic potential.…”

“…We and others have shown that pan-and class-specific HDAC inhibitors can protect DA neurons (Chen et al 2006;Chen et al 2007;Collins et al 2015;Gardian et al 2004;Kidd and Schneider 2010;Kidd and Schneider 2011;Kontopoulos et al 2006;Outeiro et al 2007;St Laurent et al 2013;Wu et al 2008;Zhu et al 2014) and sympathetic neurons (Collins et al 2015) in experimental models of PD. The potential of this approach for clinical translation is highlighted by an ongoing Phase I clinical trial of the FDA-approved drug Glycerol Phenylbutyrate (a HDAC inhibitor) which is exploring the potential of this drug to increase the removal of α-synuclein from the brain (NCT02046434) (for recent reviews see Harrison and Dexter 2013;Schneider et al 2013;Valor et al 2013).…”

“…We used neurite growth as a measure of differentiation as class-specific HDAC inhibitors have previously been shown to induce neurite growth of SH-SY5Y cells (Collins et al 2015). Having identified working concentrations of CTPB, SH-SY5Y cells were treated daily with either control (HBSS or 0.01% DMSO) or 0.5μM, 1.0μM, 2.5μM or 5μM of CTPB before being immunostained for β-actin at 4DIV, to allow visualisation of the cellular cytoskeleton, and counterstained with DAPI.…”

“…However, to our knowledge, the present study is the first to show that a selective HAT activator can induce similar neurotrophic effects in the SH-SY5Y neuronal cell line. SH-SY5Y cells have been used extensively as models of human DA and sympathetic neurons (Collins et al 2015;Hegarty et al 2013;Toulouse et al 2012;Xie et al 2010) and have been shown to be capable of differentiation into DA-synthesising neurons (Gomez-Santos et al 2002;McMillan et al 2007;Presgraves et al 2004;Xie et al 2010). In the present study, we found that CTPB-induced p300/CBP HAT activation promotes the survival and neurite growth of SH-SY5Y cells.…”