RRC ID 3408
Author Bates EA, Victor M, Jones AK, Shi Y, Hart AC.
Title Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity.
Journal J. Neurosci.
Abstract 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 Caenorhabditis elegans 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 C. elegans cAMP response element-binding protein (CREB), CREB binding protein (CBP), and histone deacetylases (HDACs) to polyglutamine-induced neurodegeneration. Deletion of CREB (crh-1) or loss of one copy of CBP (cbp-1) enhanced polyglutamine toxicity in C. elegans neurons. Loss of function alleles and RNAi were then used to systematically reduce function of each C. elegans HDAC. Generally, knockdown of individual C. elegans HDACs enhanced Htn-Q150 toxicity, but knockdown of C. elegans hda-3 suppressed toxicity. Neuronal expression of hda-3 restored Htn-Q150 toxicity and suggested that C. elegans HDAC3 (HDA-3) acts within neurons to promote degeneration in response to Htn-Q150. Genetic epistasis experiments suggested that HDA-3 and CRH-1 (C. elegans CREB homolog) directly oppose each other in regulating transcription of genes involved in polyglutamine toxicity. hda-3 loss of function failed to suppress increased neurodegeneration in hda-1/+;Htn-Q150 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.
Volume 26(10)
Pages 2830-8
Published 2006-3-8
DOI 10.1523/JNEUROSCI.3344-05.2006
PII 26/10/2830
PMID 16525063
PMC PMC6675170
MeSH Aging / physiology Animals Animals, Genetically Modified CREB-Binding Protein / metabolism Caenorhabditis elegans / cytology Caenorhabditis elegans / drug effects* Caenorhabditis elegans / enzymology Carbocyanines Cyclic AMP Response Element-Binding Protein / metabolism Disease Models, Animal Enzyme Inhibitors / pharmacology Gene Expression / physiology Histone Deacetylases / classification Histone Deacetylases / physiology* Humans Huntingtin Protein Huntington Disease / genetics Huntington Disease / metabolism* Huntington Disease / pathology Hydroxamic Acids / pharmacology Nerve Degeneration / genetics Nerve Degeneration / metabolism Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism* Neurons / drug effects* Neurons / metabolism Nuclear Proteins / genetics Nuclear Proteins / metabolism* Peptides / metabolism Peptides / toxicity* RNA Interference / physiology RNA, Messenger / metabolism Reverse Transcriptase Polymerase Chain Reaction / methods
IF 6.074
Times Cited 90
C.elegans tm1374