title: Region-specific pro-survival signaling and global neuronal protection by wild-type Huntingtin.
abstract: BACKGROUND
  Huntington's disease (HD), caused by polyglutamine expansion in huntingtin (Htt), results in severe neurodegeneration in the striatum, and to a lesser extent, cortex and hippocampus. In contrast, non-expanded huntingtin (wildtype, wtHtt) enhances pro-survival trophic factor BDNF expression and protects striatal neurons from excitotoxicity, a mechanism thought to contribute to HD pathophysiology; however, it is unknown whether these effects of wtHtt extend to other brain areas.
  
  
  OBJECTIVE
  Test wtHtt's role in pro-survival signaling and neuroprotection in striatum, cortex and hippocampus.
  
  
  METHODS
  Levels of nuclear phosphorylated cAMP response element-binding protein (pCREB), a regulator of pro-survival gene transcription, and resistance to NMDA-induced apoptosis in primary neuronal cultures - hippocampal and corticostriatal co-culture -were assessed using immunocytochemistry and excitotoxicity assays, respectively. Cultures from wild-type FVB/N (WT) mice were compared with those from YAC18 mice on an FVB/N background, expressing both human, full-length wtHtt and normal levels of murine Htt.
  
  
  RESULTS
  Basal pCREB was higher in YAC18 striatal but not cortical or hippocampal neurons; however, all three types showed decreased apoptosis in YAC18 vs. WT cultures. Increased striatal neuronal pCREB required wtHtt overexpression in both cortical and striatal neurons. Reduced response to exogenous BDNF, or its soluble scavenger TrkB-Fc, suggested enhanced BDNF signaling contributes to increased YAC18 striatal pCREB.
  
  
  CONCLUSIONS
  Basal pro-survival signaling does not predict neuronal vulnerability to apoptosis in our culture system, since wtHtt overexpression elevates basal pCREB selectively in striatal neurons but is more globally neuroprotective. These results extend knowledge of the physiological roles of huntingtin, facilitating development of HD therapeutics.
authors.affiliation: Graduate Program in Neuroscience, The University of British Columbia, Vancouver, Canada Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada.
authors.forename: Caodu
authors.initials: C
authors.lastname: Buren
authors.affiliation: Graduate Program in Neuroscience, The University of British Columbia, Vancouver, Canada Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Graduate Program in Neuroscience, The University of British Columbia, Vancouver, Canada Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Smith-Dijak
authors.affiliation: Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D016202:N-Methylaspartate
keywords: Wild-type huntingtin; excitotoxicity; neuroprotection; pCREB