Histone deacetylase inhibitors reduce polyglutamine toxicity.
Polyglutamine diseases include at least nine neurodegenerative disorders, each caused by a CAG repeat expansion in a different gene. Accumulation of mutant polyglutamine-containing proteins occurs in patients, and evidence from cell culture and animal experiments suggests the nucleus as a site of pathogenesis. To understand the consequences of nuclear accumulation, we created a cell culture system with nuclear-targeted polyglutamine. In our system, cell death can be mitigated by overexpression of full-length cAMP response element binding protein (CREB)-binding protein (CBP) or its amino-terminal portion alone. CBP is one of several histone acetyltransferases sequestered by polyglutamine inclusions. We found histone acetylation to be reduced in cells expressing mutant polyglutamine. Reversal of this hypoacetylation, which can be achieved either by overexpression of CBP or its amino terminus or by treatment with deacetylase inhibitors, reduced cell loss. These findings suggest that nuclear accumulation of polyglutamine can lead to altered protein acetylation in neurons and indicate a novel therapeutic strategy for polyglutamine disease.
McCampbell
A
A
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 3B14, 10 Center Drive, Bethesda, MD 20892, USA.
Taye
A A
AA
Whitty
L
L
Penney
E
E
Steffan
J S
JS
Fischbeck
K H
KH
D000818:Animals; D050882:CREB-Binding Protein; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011944:Receptors, Androgen / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014162:Transfection
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; D010455:Peptides; D011944:Receptors, Androgen; D015534:Trans-Activators; C097188:polyglutamine; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse