Bowel Dysfunction in Wolfram Syndrome

Zhi, Liu; Sakakibara, Ryuji; Uchiyama, Tomoyuki; Yamamoto, Tatsuya; Ito, Takashi; Ito, Shingo; Awa, Yusuke; Odaka, Takeo; Yamaguchi, Taketo; Hattori, Takamichi

doi:10.2337/diacare.29.02.06.dc05-2049

Cited by 10 publications

(5 citation statements)

References 4 publications

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“…Finally, MTC1 is the most abundantly expressed lactate transporter in peripheral nerves and its inactivation in Schwann cells leads to hypomyelination and functional deficits in sensory, but not motor, peripheral nerves ( Jha et al, 2020 ). Intriguingly, WS1 patients might develop peripheral neuropathy with increased impairment of the sensory component ( Liu et al, 2006 ). Future studies are warranted to determine lactate metabolism dysregulation in brain and peripheral neurons in Wfs1 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

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

Rossi

Ordazzo

Vanni

et al. 2023

eLife

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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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Section: Discussionmentioning

confidence: 99%

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

Rossi

Ordazzo

Vanni

et al. 2023

eLife

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“…Gastrointestinal tract involvement is an unrecognized and often neglected facet of this syndrome. Authors have mainly reported bowel dysmotility (24%) (2), symptoms of gastroparesis (29%) (8), and bowel incontinence due to sphincter weakness (85) as gastrointestinal manifestations of this illness. Videomanometric studies in one patient has shown absence of spontaneous phasic rectal contractions, suggestive of damage to the pacemaker cells in the myentric plexus (85).…”

Section: Clinical Featuresmentioning

confidence: 99%

Wolfram syndrome: important implications for pediatricians and pediatric endocrinologists

Kumar

2010

Pediatric Diabetes

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“…Intriguingly, WS1 patients might develop peripheral neuropathy with increased impairment of the sensory component (Liu et al, 2006). Future studies are warranted to determine lactate metabolism dysregulation in brain and peripheral neurons in Wfs1 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

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

Rossi

Ordazzo

Vanni

et al. 2022

Preprint

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SummaryWolfram 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.

show abstract

Bowel Dysfunction in Wolfram Syndrome

Cited by 10 publications

References 4 publications

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

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

Wolfram syndrome: important implications for pediatricians and pediatric endocrinologists

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

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