{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:43:19Z","timestamp":1790232199969,"version":"4.1.0"},"reference-count":61,"publisher":"Society for Neuroscience","issue":"10","license":[{"start":{"date-parts":[[2006,9,8]],"date-time":"2006-09-08T00:00:00Z","timestamp":1157673600000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2006,3,8]]},"abstract":"<jats:p>Expansion of a polyglutamine tract in the huntingtin protein causes neuronal degeneration and death in Huntington's disease patients, but the molecular mechanisms underlying polyglutamine-mediated cell death remain unclear. Previous studies suggest that expanded polyglutamine tracts alter transcription by sequestering glutamine rich transcriptional regulatory proteins, thereby perturbing their function. We tested this hypothesis in<jats:italic>Caenorhabditis elegans<\/jats:italic>neurons expressing a human huntingtin fragment with an expanded polyglutamine tract (Htn-Q150). Loss of function alleles and RNA interference (RNAi) were used to examine contributions of<jats:italic>C. elegans<\/jats:italic>cAMP response element-binding protein (CREB), CREB binding protein (CBP), and histone deacetylases (HDACs) to polyglutamine-induced neurodegeneration. Deletion of CREB (<jats:italic>crh-1<\/jats:italic>) or loss of one copy of CBP (<jats:italic>cbp-1<\/jats:italic>) enhanced polyglutamine toxicity in<jats:italic>C. elegans<\/jats:italic>neurons. Loss of function alleles and RNAi were then used to systematically reduce function of each<jats:italic>C. elegans<\/jats:italic>HDAC. Generally, knockdown of individual<jats:italic>C. elegans<\/jats:italic>HDACs enhanced Htn-Q150 toxicity, but knockdown of<jats:italic>C. elegans hda-3<\/jats:italic>suppressed toxicity. Neuronal expression of<jats:italic>hda-3<\/jats:italic>restored Htn-Q150 toxicity and suggested that<jats:italic>C. elegans HDAC3<\/jats:italic>(HDA-3) acts within neurons to promote degeneration in response to Htn-Q150. Genetic epistasis experiments suggested that HDA-3 and CRH-1 (<jats:italic>C. elegans<\/jats:italic>CREB homolog) directly oppose each other in regulating transcription of genes involved in polyglutamine toxicity.<jats:italic>hda-3<\/jats:italic>loss of function failed to suppress increased neurodegeneration in<jats:italic>hda-1\/+;Htn-Q150<\/jats:italic>animals, indicating that HDA-1 and HDA-3 have different targets with opposing effects on polyglutamine toxicity. Our results suggest that polyglutamine expansions perturb transcription of CREB\/CBP targets and that specific targeting of HDACs will be useful in reducing associated neurodegeneration.<\/jats:p>","DOI":"10.1523\/jneurosci.3344-05.2006","type":"journal-article","created":{"date-parts":[[2006,3,8]],"date-time":"2006-03-08T19:27:43Z","timestamp":1141846063000},"page":"2830-2838","source":"Crossref","is-referenced-by-count":111,"title":["Differential Contributions of<i>Caenorhabditis elegans<\/i>Histone Deacetylases to Huntingtin Polyglutamine Toxicity"],"prefix":"10.1523","volume":"26","author":[{"given":"Emily A.","family":"Bates","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Victor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana 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