AI Article Synopsis
- Huntington's disease is linked to a faulty huntingtin protein that has an expanded polyglutamine stretch, leading to cell damage and a decrease in the CREB binding protein (CBP).
- Research using single-cell assays shows that in cells with mutant huntingtin, the toxicity is connected to a depletion of CBP rather than just its aggregation.
- Restoring CBP levels can reverse both the reduction of acetylated histones and the resulting cell toxicity, indicating that CBP dysfunction plays a significant role in the disease's neurotoxicity.
Article Abstract
Huntington's disease is a neurodegenerative disease caused by an expanded polyglutamine stretch within the huntingtin protein. Transfection of mutant huntingtin causes cell toxicity and depletion of CREB binding protein (CBP) or its recruitment into huntingtin aggregates. However, the role of CBP has been controversial and the relationship between polyglutamine-induced toxicity and CBP depletion has not been examined on an individual cell basis. Using a single-cell based assay, we found that, in HT22 cells or primary neurons transfected with mutant huntingtin, cell toxicity was accompanied by CBP depletion, rather than merely recruitment. Transfection with a htt exon1 construct containing uninterrupted polyglutamine or a polyglutamine region engineered to form a compact beta structure resulted in cell toxicity. CBP depletion was accompanied by histone hypo-acetylation. CBP overexpression rescued both acetylated histone levels and cell toxicity. These data suggest that CBP dysfunction and altered gene transcription contribute to mutant htt-induced neurotoxicity.
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| http://dx.doi.org/10.1016/j.nbd.2006.04.011 | DOI Listing |
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