Histone deacetylase inhibitors: a novel therapeutic approach to Huntington's disease (complex mechanism of neuronal death).
Huntington's disease is an autosomal dominantly inherited neurodegenerative disorder caused by a polyglutamine repeat expansion. The onset of HD leads to problems with movement, cognition, and behavioral functioning and there is currently no effective treatment. The mechanism by which mutant huntingtin causes neuronal dysfunction is not known. However, multiple pathologic mechanisms have been discovered. Recent studies provide strong evidence for transcriptional dysregulation as a mechanism of HD pathogenesis. The control of eukaryotic gene expression depends on the modification of histone proteins associated with specific genes; acetylation and deacetylation of histones play a critical role in gene expression. Studies in numerous HD models have shown that mutant huntingtin expression leads to a change in histone acetyl transferase (HAT) activity and suggest that aberrant HAT activity may be an underlying mechanism of transcriptional dysregulation in HD. Furthermore, recent studies have shown a therapeutic role for histone deacetylase (HDAC) inhibitors in a number of HD models. In this review we discuss a number of studies that use HDAC inhibitors as therapeutic agents in HD models. These studies demonstrate that HDAC inhibitors are a promising therapeutic approach for the treatment of HD.
Sadri-Vakili
Ghazaleh
G
Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114-2001, Charlestown, MA 02129-4404, USA.
Cha
Jang-Ho J
JH
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; C086055:HTT protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D006655:Histone Deacetylases