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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-? (A?), 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 A?42 oligomers. However, supplementing SUMOylation via transduction of its conjugating enzyme, Ubc9, rescued A?-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.

SUBMITTER: Lee L 

PROVIDER: S-EPMC4250909 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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

Lee Linda L   Dale Elena E   Staniszewski Agnes A   Zhang Hong H   Saeed Faisal F   Sakurai Mikako M   Fa' Mauro M   Orozco Ian I   Michelassi Francesco F   Akpan Nsikan N   Lehrer Helena H   Arancio Ottavio O  

Scientific reports 20141202


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,  ...[more]

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