Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents.
Acetylation and deacetylation of histone protein plays a critical role in regulating gene expression in a host of biological processes including cellular proliferation, development, and differentiation. Accordingly, aberrant acetylation and deacetylation resulting from the misregulation of histone acetyltransferases (HATs) and/or histone deacetylases (HDACs) has been linked to clinical disorders such as Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, and various cancers. Of significant import has been the development of small molecule HDAC inhibitors that permit pharmacological manipulation of histone acetylation levels and treatment of some of these diseases including cancer. In this Review we discuss evidence that aberrant HAT and HDAC activity may also be a common underlying mechanism contributing to neurodegeneration during acute and chronic neurological diseases, including stroke, Huntington's disease Amyotrophic Lateral Sclerosis and Alzheimer's disease. With this in mind, a number of studies examining the use of HDAC inhibitors as therapy for restoring histone acetylation and transcriptional activation in in vitro and in vivo neurodegenerative models are discussed. These studies demonstrate that pharmacological HDAC inhibition is a promising therapeutic approach for the treatment of a range of central nervous system disorders.
Langley
Brett
B
Burke Medical Research Institute, White Plains, NY 10605, USA. blangley@burke.org
Gensert
Joann M
JM
Beal
M Flint
MF
Ratan
Rajiv R
RR
D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology*; D002843:Chromatin / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009422:Nervous System Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D013312:Stress, Physiological / Q000188:drug therapy / Q000201:enzymology
D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases