Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease.

TitleRegulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2014
AuthorsLee L, Dale E, Staniszewski A, Zhang H, Saeed F, Sakurai M, Fa' M, Orozco I, Michelassi F, Akpan N, Lehrer H, Arancio O
JournalSci Rep
Volume4
Pagination7190
Date Published2014 Dec 02
ISSN2045-2322
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Animals, Cognition, Disease Models, Animal, Hippocampus, Humans, Long-Term Potentiation, Male, Memory, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Neuronal Plasticity, SUMO-1 Protein, Sumoylation
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.

DOI10.1038/srep07190
Alternate JournalSci Rep
PubMed ID25448527
PubMed Central IDPMC4250909
Grant ListR01 NS049442 / NS / NINDS NIH HHS / United States
NS049442 / NS / NINDS NIH HHS / United States

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