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ORIGINAL RESEARCH article

Front. Cell. Neurosci.
Sec. Non-Neuronal Cells
Volume 18 - 2024 | doi: 10.3389/fncel.2024.1437995
This article is part of the Research Topic The Role of Glia in Ataxia and other Neurodegenerative Disorders View all articles

SUMO2 rescues neuronal and glial cells from the toxicity of P301L mutant Tau

Provisionally accepted
Franca Orsini Franca Orsini 1Rosaria Pascente Rosaria Pascente 1Annacarla Martucci Annacarla Martucci 1Sara Palacino Sara Palacino 1Paul Fraser Paul Fraser 2,3Ottavio Arancio Ottavio Arancio 4Luana Fioriti Luana Fioriti 1,4*
  • 1 Department of Neuroscience, Mario Negri Pharmacological Research Institute (IRCCS), Milano, Lombardy, Italy
  • 2 Tanz Centre for Research on Neurodegenerative Diseases, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 3 Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 4 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, United States

The final, formatted version of the article will be published soon.

    Abnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimer's disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD). Tau deposits primarily affect neurons, but evidence indicates that glial cells may also be affected and contribute distinctively to disease progression. Cells can respond to toxic insults by orchestrating global changes in posttranslational modifications of their proteome. Previous studies suggest that SUMOylation, a posttranslational modification consisting of conjugation of SUMO (Small ubiquitin-like modifier) to target proteins, was decreased in the hippocampus of AD patients and in animal model of AD compared with controls. This decrease in SUMOylation was correlated with increased Tau pathology and cognitive decline. Other studies have reported increased levels of SUMO in AD brains. The goal of our study was to evaluate whether SUMO conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant Tau P301L, in neurons and in glial cells. We used viral approaches to express mutant Tau P301L and SUMO2 in the hippocampus of wildtype mice. We assessed Tau distribution by immunostaining and Tau aggregation by insolubility assays followed by western blotting. We assessed neuronal toxicity and performed cell count and shape descriptor analyses on astrocytes and microglial cells. We found that mutant Tau P301L, when expressed exclusively in neurons, is toxic not only to neurons but also to glial cells, and that SUMO2 counteracts Tau P301L toxicity in neurons as well as in glia. Our results uncover an endogenous neuroprotective mechanism, whereby SUMO2 conjugation reduces Tau neuropathology and protects against toxic effects of Tau in glial cells.

    Keywords: Tau1, neuron2, astrocytes3, microglia4, SUMO5, AAV6. (Min.5-Max. 8

    Received: 24 May 2024; Accepted: 20 Nov 2024.

    Copyright: © 2024 Orsini, Pascente, Martucci, Palacino, Fraser, Arancio and Fioriti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Luana Fioriti, Department of Neuroscience, Mario Negri Pharmacological Research Institute (IRCCS), Milano, 20156, Lombardy, Italy

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