title: Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease.
abstract: Learning and memory and the underlying cellular correlate, long-term synaptic plasticity, involve regulation by posttranslational modifications (PTMs). Here we demonstrate that conjugation with the small ubiquitin-like modifier (SUMO) is a novel PTM required for normal synaptic and cognitive functioning. Acute inhibition of SUMOylation impairs long-term potentiation (LTP) and hippocampal-dependent learning. Since Alzheimer's disease (AD) prominently features both synaptic and PTM dysregulation, we investigated SUMOylation under pathology induced by amyloid-β (Aβ), a primary neurotoxic molecule implicated in AD. We observed that SUMOylation is dysregulated in both human AD brain tissue and the Tg2576 transgenic AD mouse model. While neuronal activation normally induced upregulation of SUMOylation, this effect was impaired by Aβ42 oligomers. However, supplementing SUMOylation via transduction of its conjugating enzyme, Ubc9, rescued Aβ-induced deficits in LTP and hippocampal-dependent learning and memory. Our data establish SUMO as a novel regulator of LTP and hippocampal-dependent cognition and additionally implicate SUMOylation impairments in AD pathogenesis.
authors.affiliation: 1] Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA [2] Department of Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Lee
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Dale
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Staniszewski
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Faisal
authors.initials: F
authors.lastname: Saeed
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Mikako
authors.initials: M
authors.lastname: Sakurai
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Fa'
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Orozco
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Michelassi
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Nsikan
authors.initials: N
authors.lastname: Akpan
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Lehrer
authors.affiliation: Taub Institute and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000502:physiology*; D025842:SUMO-1 Protein / Q000378:metabolism*; D058207:Sumoylation / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D025842:SUMO-1 Protein