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.

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

“…This, combined with the unfolded protein response observed in the retina and optic nerve, suggests that we are looking at the earliest stages of disease, during which neuronal dysfunction is accumulating, but has not yet reached the tipping point towards cellular loss. Indeed, our findings confirm previous results in the same mouse model, in which neurodegeneration of the retinal ganglion cells was not seen at 8 months but manifested at 12 months [59], and mirror a study in WS patients, in which it was found that retinal ganglion cell axonal degeneration precedes cell body atrophy by about a decade [5]. Given the detrimental phenotype of this transgenic model, and applying humane end points, we limited our study to a maximum age of 7.5 months.…”

“…At this age, we observed a mild and complex disease phenotype in the optic nerve, with alterations in axonal conduction strength combined with subtle thinning of the myelin sheath and a reduction of the OPC pool. Again, these findings are in line with a previous study in this Wfs1 Dexon8 mouse model [59], as well as in Wfs1 Dexon2 mouse and Wfs1 Dexon5 rat models [7,53]. Novel findings in our study originate from ex vivo measurements of optic nerve CAPs, which allowed us to investigate a potential defect in the optic nerve while excluding the retinal ganglion cell bodies and synapses.…”

“…In the Wfs1 Λ1exon8 mouse model, disturbances in the dopaminergic and GABAergic system, together with changes in motor function and anxiety have been described, thereby mirroring the motor and psychiatric problems seen in patients [42, 56, 71]. Furthermore, a recent study by Rossi et al reported that retinal degeneration and vision loss in the Wfs1 Λ1exon8 mouse model is preceded by loss of glial homeostasis, MCT1-dependent metabolic dysfunction and myelin derangement in the optic nerve [59]. While these studies all find a clear neurodegenerative phenotype, they also show white matter defects, hence raising the question whether the neurodegenerative component of WS could be mainly driven by an oligodendroglia rather than a neuronal pathology.…”

Genomics of Wolfram Syndrome 1 (WFS1)

“…The mouse model for the WFS1 syndrome that lacked two-thirds of the WFS1 gene reproduced all clinical features of this complex disease, like diabetes and mental disorders [ 47 ]. Within many years, several studies based on this mouse model have been published to describe the variable phenotypic effects of the mutation [ 57 , 58 ]. Very briefly, we have identified the growth retardation and development of combined endocrine disorders, combined with diabetes, in WFS1 mutant mice [ 39 , 48 , 50 , 59 ].…”

ER Calcium Depletion as a Key Driver for Impaired ER-to-Mitochondria Calcium Transfer and Mitochondrial Dysfunction in Wolfram Syndrome

“…Therefore, we hypothesized that a lack of su cient PDH activity in WFS1 and CISD2 de cient neurons might diminish mitochondrial ATP production and, consequently, push the neuronal metabolism toward glycolysis. Indeed, several lines of indirect evidence suggest that a similar mechanism might be involved in WS 10,31,32 . First, the mitochondrial membrane potential, which re ects the e ciency of the NADHpowered mitochondrial respiratory chain, was slightly lower in WFS1-and CISD2-de cient neurons (Fig.…”