Multiple roles of HDAC inhibition in neurodegenerative conditions

Abstract

Histone deacetylases (HDACs) play a key role in homeostasis of protein acetylation in histones and other proteins and in regulating fundamental cellular activities such as transcription. A wide range of brain disorders are associated with imbalances in protein acetylation levels and transcriptional dysfunctions. Treatment with various HDAC inhibitors can correct these deficiencies and has emerged as a promising new strategy for therapeutic intervention in neurodegenerative disease. Here, we review and discuss intriguing recent developments in the use of HDAC inhibitors to combat neurodegenerative conditions in cellular and disease models. HDAC inhibitors have neuroprotective, neurotrophic and anti-inflammatory properties; improvements in neurological performance, learning/memory and other disease phenotypes are frequently seen in these models. We discuss the targets and mechanisms underlying these effects of HDAC inhibition and comment on the potential for some HDAC inhibitors to prove clinically effective in the treatment of neurodegenerative disorders.

Figure 1. The effects of HDAC inhibitors on chromatin remodeling

Levels of histone acetylation at Lys residues on histone tails are determined by interplays of acetylation and deacetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Inhibition of HDACs by HDAC inhibitors results in a net increase in histone acetylation levels and a more open, relaxed chromatin conformation which favors transcriptional activation. By contrast, chromatin with a compact conformation is transcriptionally inactive. : acetylated Lys residues of histone-tail proteins.

Figure 2. The actions of HDAC inhibitors in neurodegenerative conditions

A large number of neurodegenerative conditions in vivo and in vitro involve functional imbalance in HATs and HDACs, resulting in histone hypoacetylation and transcriptional dysfunction. Treatment with Class I, II and, more recently, III HDAC inhibitors restores these deficiencies. These effects appear to be mediated by multiple HDAC-regulated gene products including BDNF, GDNF, HSP70, α-synuclein, Bcl-2, Bcl-X_L, p21, and gelsolin, among others. Non-transcriptional effects of HDAC inhibitors, such as hyperacetylation and stabilization of microtubule proteins, have also been shown in many neurodegenerative disease models. Studies suggest that HDAC inhibitors have neuroprotective, neurotrophic, and anti-inflammatory effects, as well as improve neurological performance and learning/memory in various neurodegenerative conditions. Bcl-2: B-cell lymphoma 2; BDNF: brain-derived neurotrophic factor; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GDNF: glial cell line-derived neurotrophic factor; HAT: histone acetyltransferase; HDAC: histone deacetylase; HSP70: heat shock protein 70.