RT Journal Article
SR Electronic
T1 MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.18.500452
DO 10.1101/2022.07.18.500452
A1 Greta Rossi
A1 Gabriele Ordazzo
A1 Niccolò N. Vanni
A1 Valerio Castoldi
A1 Angelo Iannielli
A1 Dario Di Silvestre
A1 Edoardo Bellini
A1 Letizia Bernardo
A1 Serena G. Giannelli
A1 Sharon Muggeo
A1 Leocani Letizia
A1 PierLuigi Mauri
A1 Vania Broccoli
YR 2022
UL http://biorxiv.org/content/early/2022/07/20/2022.07.18.500452.abstract
AB 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 astrocytes 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 in 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.Competing Interest StatementThe authors have declared no competing interest.