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.

Keywords::

• histone deacetylase inhibitors
• histone deacetylases
• neurodegeneration
• therapeutics
• transcription

Acknowledgements

We would like to thank A Siddiq for her critical reading of this review and also MA Rivieccio and C Brochier for their suggestions. We acknowledge the support of the Adelson Foundation (CO #190772), the New York State Department of Health, NIA PO1, the Burke Foundation and the Goldsmith Foundation.

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