Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila.
Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms.
Steffan
J S
JS
Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, California 92697, USA.
Bodai
L
L
Pallos
J
J
Poelman
M
M
McCampbell
A
A
Apostol
B L
BL
Kazantsev
A
A
Schmidt
E
E
Zhu
Y Z
YZ
Greenwald
M
M
Kurokawa
R
R
Housman
D E
DE
Jackson
G R
GR
Marsh
J L
JL
Thompson
L M
LM
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D050882:CREB-Binding Protein; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation; D005973:Glutamine / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D016716:PC12 Cells; D010455:Peptides / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D020449:Repetitive Sequences, Amino Acid; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D015534:Trans-Activators / Q000378:metabolism*
D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D005973:Glutamine; C097188:polyglutamine; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; D051548:Histone Acetyltransferases; D005982:Glutathione Transferase; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex