title: Increased EID1 nuclear translocation impairs synaptic plasticity and memory function associated with pathogenesis of Alzheimer's disease.
abstract: Though loss of function in CBP/p300, a family of CREB-binding proteins, has been causally associated with a variety of human neurological disorders, such as Rubinstein-Taybi syndrome, Huntington's disease and drug addiction, the role of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, in modulating neurological functions remains completely unknown. Through the examination of EID1 expression and cellular distribution, we discovered that there is a significant increase of EID1 nuclear translocation in the cortical neurons of Alzheimer's disease (AD) patient brains compared to that of control brains. To study the potential effects of EID1 on neurological functions associated with learning and memory, we generated a transgenic mouse model with a neuron-specific expression of human EID1 gene in the brain. Overexpression of EID1 led to an increase in its nuclear localization in neurons mimicking that seen in human AD brains. The transgenic mice had a disrupted neurofilament organization and increase of astrogliosis in the cortex and hippocampus. Furthermore, we demonstrated that overexpression of EID1 reduced hippocampal long-term potentiation and impaired spatial learning and memory function in the transgenic mice. Our results indicated that the negative effects of extra nuclear EID1 in transgenic mouse brains are likely due to its inhibitory function on CBP/p300 mediated histone and p53 acetylation, thus affecting the expression of downstream genes involved in the maintenance of neuronal structure and function. Together, our data raise the possibility that alteration of EID1 expression, particularly the increase of EID1 nuclear localization that inhibits CBP/p300 activity in neuronal cells, may play an important role in AD pathogenesis.
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Rugao
authors.initials: R
authors.lastname: Liu
authors.forename: Joy X
authors.initials: JX
authors.lastname: Lei
authors.forename: Chun
authors.initials: C
authors.lastname: Luo
authors.forename: Xun
authors.initials: X
authors.lastname: Lan
authors.forename: Liying
authors.initials: L
authors.lastname: Chi
authors.forename: Panyue
authors.initials: P
authors.lastname: Deng
authors.forename: Saobo
authors.initials: S
authors.lastname: Lei
authors.forename: Othman
authors.initials: O
authors.lastname: Ghribi
authors.forename: Qing Yan
authors.initials: QY
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000473:pathology; D004558:Electric Stimulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D018782:Maze Learning / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010750:Phosphoproteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018243:Teratocarcinoma / Q000473:pathology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C416925:EID1 protein, human; D005904:Glial Fibrillary Acidic Protein; D006657:Histones; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009687:Nuclear Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D010751:Phosphopyruvate Hydratase