Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway.
Oxidative stress is believed to be an important mediator of neurodegeneration. However, the transcriptional pathways induced in neurons by oxidative stress that activate protective gene responses have yet to be fully delineated. We report that the transcription factor Sp1 is acetylated in response to oxidative stress in neurons. Histone deacetylase (HDAC) inhibitors augment Sp1 acetylation, Sp1 DNA binding, and Sp1-dependent gene expression and confer resistance to oxidative stress-induced death in vitro and in vivo. Sp1 activation is necessary for the protective effects of HDAC inhibitors. Together, these results demonstrate that HDAC inhibitors inhibit oxidative death independent of polyglutamine expansions by activating an Sp1-dependent adaptive response.
Ryu
Hoon
H
Department of Neurology and Program in Neuroscience, Harvard Medical School and Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Lee
Junghee
J
Olofsson
Beatrix A
BA
Mwidau
Aziza
A
Dedeoglu
Alpaslan
A
Escudero
Maria
M
Flemington
Erik
E
Azizkhan-Clifford
Jane
J
Ferrante
Robert J
RJ
Ratan
Rajiv R
RR
Deodoglu
Alpaslan
A
D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C097188:polyglutamine