Histone deacetylases as targets for the treatment of human neurodegenerative diseases

Abstract

Histone deacetylases (HDACs) are a family of proteins that play an important role in regulating transcription as well as the function of a variety of cellular proteins. While these proteins are expressed abundantly in the brain, little is known about their roles in brain function. A growing body of evidence suggests that HDACs regulate neuronal survival. Results from studies conducted in vertebrate and mammalian experimental systems indicate that while some of these proteins are involved in promoting neuronal death, a majority of the HDACs studied thus far protect against neurodegeneration. Here we review the research performed on the role played by individual members of the HDAC family in the regulation of neuronal death. Chemical inhibitors of HDACs have been used in a variety of models of neurodegenerative disorders. We summarize the results from these studies, which indicate that HDAC inhibitors show great promise as therapeutic agents for human neurodegenerative disorders.

Figure 1

The histone deacetylase (HDAC) family of proteins. The conserved deacetylase domain of the classical HDACs (blue rectangles), deacetylase domain of the sirtuins (purple rectangles) and the ADP-ribosyl transferase catalytic domain (red rectangles) are indicated. Histone deacetylase-related protein (HDRP), also referred to as MITR, is a truncated form of HDAC9, generated by alternative splicing. SIRT2, SIRT3 and SIRT6 have both deacetylase and ADP-ribosyl transferase activities. No catalytic activity has been reported for SIRT7. The myocyte-specific enhancer factor 2A (MEF2)-binding site is marked by a blue square and the location of key serine residues that are phosphorylated, is indicated with “S”. The leucine-rich region in HDAC10 and the C-terminal zinc finger (ZnF) are also shown.