MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice
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eLife assessment
The primary goal of this paper is to characterize retinal dysfunction and retinal ganglion cell degeneration in the Wfs1exon8del murine model of Wolfram Syndrome 1. The study provides fundamental insight into the timelines of degeneration as well as valuable transcriptomic and proteomic datasets. The methodologies performed are generally rigorous and the conclusions reached are mostly well supported by the data, however, the interrogation of the mechanism is largely circumstantial and the relevance to disease is primarily speculative. The results of this study are highly relevant for molecular mechanisms in Wolfram Syndrome 1 and are of potential interest to scientists interested in oligodendrocyte and neuron communication.
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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.
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eLife assessment
The primary goal of this paper is to characterize retinal dysfunction and retinal ganglion cell degeneration in the Wfs1exon8del murine model of Wolfram Syndrome 1. The study provides fundamental insight into the timelines of degeneration as well as valuable transcriptomic and proteomic datasets. The methodologies performed are generally rigorous and the conclusions reached are mostly well supported by the data, however, the interrogation of the mechanism is largely circumstantial and the relevance to disease is primarily speculative. The results of this study are highly relevant for molecular mechanisms in Wolfram Syndrome 1 and are of potential interest to scientists interested in oligodendrocyte and neuron communication.
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Reviewer #1 (Public Review):
Wolfram syndrome 1 (WS1) is a rare genetic disorder characterized by diabetes mellitus, various neurological dysfunction, and blindness caused by optic atrophy. The primary impact of this paper is the characterization of vision loss, retinal dysfunction, and retinal ganglion cell (RGC) degeneration in the Wfs1exon8del murine model of WS1 combined with the generation of -omics datasets at RNA and protein levels. Based largely on a qualitative assessment of select targets, the authors propose mechanisms that could increase RGC susceptibility in WS1 pathology.
Strengths:
1. This study determines that Wfs1exon8del mice exhibit progressive disruption of RGC function similar to that reported in the Wfs1exon5del rat model.
2. This study performs an in-depth assessment of retinal anatomy, including in vivo OCT and …Reviewer #1 (Public Review):
Wolfram syndrome 1 (WS1) is a rare genetic disorder characterized by diabetes mellitus, various neurological dysfunction, and blindness caused by optic atrophy. The primary impact of this paper is the characterization of vision loss, retinal dysfunction, and retinal ganglion cell (RGC) degeneration in the Wfs1exon8del murine model of WS1 combined with the generation of -omics datasets at RNA and protein levels. Based largely on a qualitative assessment of select targets, the authors propose mechanisms that could increase RGC susceptibility in WS1 pathology.
Strengths:
1. This study determines that Wfs1exon8del mice exhibit progressive disruption of RGC function similar to that reported in the Wfs1exon5del rat model.
2. This study performs an in-depth assessment of retinal anatomy, including in vivo OCT and FA, which provides analysis of both vascular and neural elements of pathology.
3. TEM and immunohistochemical assessment of optic nerve anatomy and RGC soma elucidate a timeline of degenerative events that begins with myelin thinning and axon pathology followed by axon and soma loss.
4. RNA sequencing and proteomic profiling provide a global assessment of potentially relevant pathways associated with retinal and optic nerve pathology induced by Wfs1 deletion.Weaknesses:
1. Mechanisms are generally inferred from previous literature rather than demonstrated directly in this model.
2. Diverse phenotypes were noted in oligodendrocytes, astrocytes, Muller cells, and microglia. It is difficult to piece together the significance of these observations and their relationship to the RGC degeneration noted in earlier figures. There is a sense that the surface is skimmed for each of these.
3. ERG and f-VEP data do not rule out the possibility that the electrophysiological function of the retina is abnormal from birth.
4. Only positive correlations with existing literature are discussed. -
Reviewer #2 (Public Review):
The work presented aims at analyzing the effect of the loss of function of WFS1, the gene responsible for Wolfram syndrome, in visual physiology. They analyzed the vision of knock-out mice and deciphered the potential altered signaling pathways using transcriptomics and proteomics approaches. Interestingly, they identified monocarboxylate transport isoform 1 and its partner Basigin as downregulated proteins. In addition, they demonstrated that excessive neuroinflammation may contribute to the observed phenotype. These data add, in an interesting way, a novel pathophysiological mechanism leading to Wolfram syndrome.
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Reviewer #3 (Public Review):
The study titled "MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice" has illustrated one of the possible molecular mechanism of Retino-ganglion cells (RGCs) degeneration leading to optic atrophy observed in the patients of Wolfram syndrome (WS). It is very crucial to understand the molecular details of optic atrophy and progressive vision loss in patients of WS. The main reason for the optic atrophy and loss of vision in Wolfram syndrome is the degeneration of specific cells in the retina- Retino-ganglion cells (RGCs). There have been many studies in different model systems of WS but the study addressing the loss of vision is limited. A recent study in a zebrafish model of WS shows thinning of the optic nerve layer, loss of RGCs, and loss of …
Reviewer #3 (Public Review):
The study titled "MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice" has illustrated one of the possible molecular mechanism of Retino-ganglion cells (RGCs) degeneration leading to optic atrophy observed in the patients of Wolfram syndrome (WS). It is very crucial to understand the molecular details of optic atrophy and progressive vision loss in patients of WS. The main reason for the optic atrophy and loss of vision in Wolfram syndrome is the degeneration of specific cells in the retina- Retino-ganglion cells (RGCs). There have been many studies in different model systems of WS but the study addressing the loss of vision is limited. A recent study in a zebrafish model of WS shows thinning of the optic nerve layer, loss of RGCs, and loss of vision, however, the molecular mechanism for the specific degeneration of RGCs is limiting. Therefore, it is of utmost need to understand the molecular mechanism/s which could be the possible reason for the loss of RGCs in WS.
In this study, the authors have illustrated one of the possible molecular mechanisms leading to the loss of RGCs and eventually resulting in progressive loss of vision in mice models of WS. The study shows that MCT1 and Wolframin interact with each other and help in lactate transport to meet the high energy demand of RGCs. In the absence of wolfamin, MCT1 dependant energy failure leads to demyelination of optic nerve axons further leading to the degeneration of RGCs and progressive loss of vision. This study is one of its kind which investigates the molecular mechanism for the selective loss of RGCs in the wolfram syndrome. This finding will enable therapeutic screening of promising drug molecules that could rescue the RGCs degeneration.
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