MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice
- San Raffaele Scientific Institute, Italy
- Institute of Technologies in Biomedicine, Italy
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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Wolfram Syndrome retina RNA-seqNCBI Gene Expression Omnibus, GSE206150.
Article and author information
Author details
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
- Rebecca M Sappington, Wake Forest Baptist Medical Center, United States
Version history
- Received: July 11, 2022
- Preprint posted: July 20, 2022 (view preprint)
- Accepted: January 13, 2023
- Accepted Manuscript published: January 16, 2023 (version 1)
- Version of Record published: February 1, 2023 (version 2)
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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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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