MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

Abstract

Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by mutations in the WFS1 gene leading to a wide spectrum of clinical dysfunctions, among which blindness, diabetes and neurological deficits are the most prominent. WFS1 encodes for the endoplasmic reticulum (ER) resident transmembrane protein wolframin with multiple functions in ER processes. However, the WFS1-dependent etiopathology in retinal cells is unknown. Herein, we showed that Wfs1 mutant mice developed early retinal electrophysiological impairments followed by marked visual loss. Interestingly, axons and myelin disruption in the optic nerve preceded the degeneration of the retinal ganglion cell bodies in the retina. Transcriptomics at pre-degenerative stage revealed the STAT3-dependent activation of proinflammatory glial markers with reduction of the homeostatic and pro-survival factors glutamine synthetase and BDNF. Furthermore, label-free comparative proteomics identified a significant reduction of the monocarboxylate transport isoform 1 (MCT1) and its partner basigin that are highly enriched on retinal glia and myelin-forming oligodendrocytes in optic nerve together with wolframin. Loss of MCT1 caused a failure in lactate transfer from glial to neuronal cell bodies and axons leading to a chronic hypometabolic state. Thus, this bioenergetic impairment is occurring concurrently both within the axonal regions and cell bodies of the retinal ganglion cells, selectively endangering their survival while impacting less on other retinal cells. This metabolic dysfunction occurs months before the frank RGC degeneration suggesting an extended time-window for intervening with new therapeutic strategies focused on boosting retinal and optic nerve bioenergetics in WS1.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE42357.

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Article and author information

Author details

  1. Greta Rossi

    Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Gabriele Ordazzo

    Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1850-0375
  3. Niccolò N Vanni

    Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Valerio Castoldi

    Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Angelo Iannielli

    Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Dario Di Silvestre

    Institute of Technologies in Biomedicine, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Edoardo Bellini

    Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9766-7685
  8. Letizia Bernardo

    Institute of Technologies in Biomedicine, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Serena Giannelli

    Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Mirko Luoni

    Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5006-1827
  11. Sharon Muggeo

    Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7135-9780
  12. Leocani Letizia

    Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  13. PierLuigi Mauri

    Institute of Technologies in Biomedicine, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  14. Vania Broccoli

    Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
    For correspondence
    broccoli.vania@hsr.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4050-0926

Funding

Italian Ministry of Health (RF2019-12370396)

  • PierLuigi Mauri

Elixir Implementation Study Proteomics 2021-23 (EISP-23-072)

  • PierLuigi Mauri

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Rebecca M Sappington, Wake Forest Baptist Medical Center, United States

Publication history

  1. Received: July 11, 2022
  2. Accepted: January 13, 2023
  3. Accepted Manuscript published: January 16, 2023 (version 1)

Copyright

© 2023, Rossi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Greta Rossi
  2. Gabriele Ordazzo
  3. Niccolò N Vanni
  4. Valerio Castoldi
  5. Angelo Iannielli
  6. Dario Di Silvestre
  7. Edoardo Bellini
  8. Letizia Bernardo
  9. Serena Giannelli
  10. Mirko Luoni
  11. Sharon Muggeo
  12. Leocani Letizia
  13. PierLuigi Mauri
  14. Vania Broccoli
(2023)
MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice
eLife 12:e81779.
https://doi.org/10.7554/eLife.81779

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