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

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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.

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Acknowledgments

We thank Lundbeck A/S (Copenhagen, Denmark) for kindly providing Tg2576 mice samples and respective controls. This work has been financially supported by Lundbeck A/S grant and partially by ‘Ricerca Corrente 2013–2016’ from Istituto C. Mondino (Pavia, Italy).

Author information

Authors and Affiliations

  1. Laboratory of Neuronal Cell Signaling, EBRI Rita Levi-Montalcini Foundation, Rome, Italy

    Serena Marcelli, Filomena Iannuzzi & Marco Feligioni

  2. Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Milan, Italy

    Elena Ficulle & Marco Feligioni

  3. Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland

    Enikö Kövari

  4. Pharmacology of Synaptic Disease, EBRI Rita Levi-Montalcini Foundation, Rome, Italy

    Robert Nisticò

  5. University of Rome “Tor Vergata”, Rome, Italy

    Robert Nisticò

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  1. Serena Marcelli
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Correspondence to Marco Feligioni.

Additional information

Serena Marcelli and Elena Ficulle share co-first authorship.

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Fig S1

Characterization of synaptosomes from human AD brains. Representative western blots of the characterization of the synaptosomal preparation from human frozen samples. a–b Total lysate or synaptosomes have been compared by probing for nuclear. c post synaptic and d–e presynaptic proteins (JPEG 139 kb)

Fig S2

Human samples table. Information regarding human samples are here summarized: Age, Gender, Braak stage, and Diagnosis of the patients are indicated. Delay is the time between death and cerebral sampling. (JPEG 28 kb)

High resolution image (TIFF 376 kb)

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Marcelli, S., Ficulle, E., Iannuzzi, F. et al. Targeting SUMO-1ylation Contrasts Synaptic Dysfunction in a Mouse Model of Alzheimer’s Disease. Mol Neurobiol 54, 6609–6623 (2017). https://doi.org/10.1007/s12035-016-0176-9

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  • DOI: https://doi.org/10.1007/s12035-016-0176-9

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