Histone deacetylase activity is retained in primary neurons expressing mutant huntingtin protein.
Perturbation of histone acetyl-transferase (HAT) activity is implicated in the pathology of polyglutamine diseases, and suppression of the counteracting histone deacetylase (HDAC) proteins has been proposed as a therapeutic candidate for these intractable disorders. Meanwhile, it is not known whether mutant polyglutamine disease protein affects the HDAC activity in declining neurons, though the answer is essential for application of anti-HDAC drugs for polyglutamine diseases. Here, we show the effect of mutant huntingtin (htt) protein on the expression and activity of HDAC proteins in rat primary cortical neurons as well as in human Huntington's disease (HD) brains. Our findings indicate that expression and activity of HDAC proteins are not repressed by mutant htt protein. Furthermore, expression of normal and mutant htt protein slightly increased HDAC activity although the effects of normal and mutant htt were not remarkably different. In human HD cerebral cortex, HDAC5 immunoreactivity was increased in the nucleus of striatal and cortical neurons, suggesting accelerated nuclear import of this class II HDAC. Meanwhile, western blot and immunohistochemical analyses showed no remarkable change in the expression of class I HDAC proteins such as HDAC1 and HDCA8. Collectively, retained activity in affected neurons supports application of anti-HDAC drugs to the therapy of HD.
Hoshino
Masataka
M
Department of Molecular Therapeutics, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan.
Tagawa
Kazuhiko
K
Okuda
Tomohiro
T
Murata
Miho
M
Oyanagi
Kiyomitsu
K
Arai
Nobutaka
N
Mizutani
Toshio
T
Kanazawa
Ichiro
I
Wanker
Erich E
EE
Okazawa
Hitoshi
H
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000473:pathology; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C110550:HDAC1 protein, human; C404500:HDAC5 protein, human; C498619:Hdac5 protein, rat; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases