Moving toward understanding polyglutamine toxicity
Polyglutamine diseases, including Huntington’s disease, arise from multiple repeats of the glutamine codon—for example CAGCAGCAGCAG—in a variety of genes. Since these diseases likely share similar mechanisms, a better understanding of how these repeats cause dysfunction could aid in the development of therapies.
IRP researchers led by Kenneth Fischbeck, M.D., found that the expanded polyglutamine proteins may act as sticky glue, blocking up their normal clearance process. The excess protein then interferes with a number of nuclear factors important in maintaining genetic stability, causing the cell to enter apoptosis, or programmed cell death. These observations correlate with the neuronal death observed in conditions such as Huntington’s disease.
The finding that polyglutamine toxicity in cell culture may be due to interference with nuclear factors has potential therapeutic implications, and research is underway to evaluate molecules with potential application as disruptors of that process.
McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS, Fischbeck KH. (2001). Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci U S A. 98(26), 15179-84.