Putting the 'HAT' back on survival signalling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions

Abstract

Decreased histone acetyltransferase activity and transcriptional dysfunction have been implicated in almost all neurodegenerative conditions. Increasing net histone acetyltransferase activity through inhibition of the histone deacetylases (HDACs) has been shown to be an effective strategy to delay or halt progression of neurological disease in cellular and rodent models. These findings have provided firm rationale for Phase I and Phase II clinical trials of HDAC inhibitors in Huntington's disease, spinal muscular atrophy, and Freidreich's ataxia. In this review, we discuss the current findings and promise of HDAC inhibition as a strategy for treating neurological disorders. Despite the fact that HDAC inhibitors are in an advanced stage of development, we suggest other approaches to modulating HDAC function that may be less toxic and more efficacious than the canonical agents developed so far.

Figure 1

Histone deacetylase classes, expression patterns and sub-cellular localization.

Figure 2. Strategies to inhibit histone deacetylase activity

A. Recruitment of histone deacetylases (HDACs) to gene promoters followed by histone deacetylation leads to DNA compaction and repression of gene expression, whereas recruitment of histone acetyltransferases (HATs) leads to an open DNA conformation and activation of gene expression. B–E. Therapeutic strategies that involve either increasing HAT activity directly or increasing HAT activity indirectly through HDAC inhibition. B. Targeting HATs and directly increasing their activity. C. Targeting signaling pathways that induce post-translational modifications that lead to reduced target promoter binding. D. Designing peptides that can interfere with the interaction between the HDAC and the relevant corepressors and prevent recruitment of HDAC to target promoters. E. Targeting the redox state of HDACs in order to control its subcellular localization. F. Targeting HDAC activity in glia as a mechanism to protect the neurons. BDNF: Brain-derived neurotrophic factor; CoA: Coenzyme A; CoR: ; NO: Nitric oxide.

Figure 2. Strategies to inhibit histone deacetylase activity

A. Recruitment of histone deacetylases (HDACs) to gene promoters followed by histone deacetylation leads to DNA compaction and repression of gene expression, whereas recruitment of histone acetyltransferases (HATs) leads to an open DNA conformation and activation of gene expression. B–E. Therapeutic strategies that involve either increasing HAT activity directly or increasing HAT activity indirectly through HDAC inhibition. B. Targeting HATs and directly increasing their activity. C. Targeting signaling pathways that induce post-translational modifications that lead to reduced target promoter binding. D. Designing peptides that can interfere with the interaction between the HDAC and the relevant corepressors and prevent recruitment of HDAC to target promoters. E. Targeting the redox state of HDACs in order to control its subcellular localization. F. Targeting HDAC activity in glia as a mechanism to protect the neurons. BDNF: Brain-derived neurotrophic factor; CoA: Coenzyme A; CoR: ; NO: Nitric oxide.