Targeting SUMO-1ylation Contrasts Synaptic Dysfunction in a Mouse Model of Alzheimer’s Disease

Serena Marcelli, Elena Ficulle, Filomena Iannuzzi, Enikö Kövari, Robert Nisticò, Marco Feligioni

Research output: Contribution to journalArticlepeer-review

Abstract

Synaptic dysfunction has been recognized as an early feature occurring at the onset of Alzheimer’s disease (AD). Compromised neurotransmission leads over time to synaptic loss and these events correlate with the cognitive decline that progressively affects AD patients. Protein SUMOylation (Small Ubiquitin-like MOdifier) is a post-translational modification (PTM) involved in several cellular processes including synaptic transmission. We here demonstrate that cortical synaptosomes prepared from Tg2576 mice of 6 months of age show an increased SUMO-1ylation, which returns back to normal levels at 20 months although synaptic SUMOylation, at this age, resulted more sensible to KCl stimulus. Our previous findings have shown that increased SUMOylation at presynaptic level reduces the KCl-induced glutamate release. Accordingly, Tg2576 mice of 6 and 20 months show a reduced KCl-evoked neurotransmitter (NT) release. In order to target SUMOylation, we developed two cell penetrating HIV Tat-linked peptides, namely TU-1 and TS-1. This strategy allowed us to modulate the SUMO machinery either positively (TU-1) or negatively (TS-1). As expected, Tg2576 synaptosomes treated with TU-1 exhibited a reduced NT release evoked by KCl. On the contrary, TS-1 treatment, which decreased SUMOylation, was able to normalize impaired glutamate release. Notably, an analysis of autopsy human AD brains has shown an increased SUMOylation in both cortical tissue and synaptosomal lysate. Our data indicate that SUMOylation level changes contribute to the development of synaptic alterations typically occurring at the AD onset and that SUMOylation could be a pharmacological target in AD synaptic dysfunction.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalMolecular Neurobiology
DOIs
Publication statusAccepted/In press - Oct 13 2016
Externally publishedYes

Keywords

  • Alzheimer’s
  • Human samples
  • Neurotransmitter release
  • SUMO1
  • Synapses

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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