ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 21, 2024

Abstract Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect involves poor ER Ca 2+ handling, but how this disturbance leads to not known. The current study, performed neurons, most affected and disease-relevant cells, involving both genes, explains disturbed handling compromises mitochondrial function affects neuronal health. Loss of content impaired ER-mitochondrial contact sites WFS1- CISD2-deficient neurons associated with lower IP 3 R-mediated transfer from mitochondria decreased uptake. In turn, reduced inhibits ATP production leading an increased NADH/NAD + ratio. resulting bioenergetic deficit reductive stress compromise health neurons. Our work also identifies pharmacological targets compounds that restore homeostasis, enhance improve

Language: Английский

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Genomics of Wolfram Syndrome 1 (WFS1)

Biomolecules, Journal Year: 2023, Volume and Issue: 13(9), P. 1346 - 1346

Published: Sept. 4, 2023

Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It characterised by diabetes insipidus, mellites, optic atrophy, and deafness and, therefore, also known as DIDMOAD. Nearly 15,000-30,000 people are affected WFS worldwide, on average, patients suffering from die at 30 years of age, usually central respiratory failure caused massive brain atrophy. The more prevalent the two kinds WFS1, which monogenic disease loss WFS1 gene, whereas WFS2, uncommon, mutations in CISD2 gene. Currently, there no treatment for to increase life expectancy patients, treatments available do not significantly improve their quality life. Understanding genetics molecular mechanisms essential finding cure. inability conventional medications treat points need innovative strategies must address fundamental cause: deletion gene leads profound ER stress disturbances proteostasis. An important approach here understand mechanism cell degeneration after describe differences these different tissues. studies so far have indicated remarkable clinical heterogeneity variable vulnerability mutations, cannot be attributed solely positions present review gives broader overview results genomic mouse model.

Language: Английский

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

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Jan. 16, 2023

Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by mutations in the WFS1 gene leading to wide spectrum of clinical dysfunctions, among which blindness, diabetes, and neurological deficits are most prominent. encodes for endoplasmic reticulum (ER) resident transmembrane protein wolframin with multiple functions ER processes. However, -dependent etiopathology retinal cells unknown. Herein, we showed that Wfs1 mutant mice developed early electrophysiological impairments followed marked visual loss. Interestingly, axons myelin disruption optic nerve preceded degeneration ganglion cell bodies retina. Transcriptomics at pre-degenerative stage revealed STAT3-dependent activation proinflammatory glial markers reduction homeostatic pro-survival factors glutamine synthetase BDNF. Furthermore, label-free comparative proteomics identified significant monocarboxylate transport isoform (MCT1) its partner basigin highly enriched on glia myelin-forming oligodendrocytes together wolframin. Loss MCT1 failure lactate transfer from neuronal chronic hypometabolic state. Thus, this bioenergetic impairment occurring concurrently both within axonal regions cells, selectively endangering their survival while impacting less other cells. This metabolic dysfunction occurs months before frank RGC suggesting an extended time-window intervening new therapeutic strategies focused boosting bioenergetics WS1.

Language: Английский

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Insights into cargo sorting by SNX32 and its role in neurite outgrowth

eLife, Journal Year: 2023, Volume and Issue: 12

Published: May 9, 2023

Sorting nexins (SNX) are a family of proteins containing the Phox homology domain, which shows preferential endo-membrane association and regulates cargo sorting processes. Here, we established that SNX32, an SNX-BAR (Bin/Amphiphysin/Rvs) sub-family member associates with SNX4 via its BAR domain residues A226, Q259, E256, R366 Y258, S448 lie at interface these two SNX mediate this association. PX interacts transferrin receptor (TfR) Cation-Independent Mannose-6-Phosphate Receptor (CIMPR), conserved F131 in is important stabilizing interactions. Silencing SNX32 leads to defect intracellular trafficking TfR CIMPR. Further, using SILAC-based differential proteomics wild-type mutant impaired binding, identified Basigin (BSG), immunoglobulin superfamily member, as potential interactor SHSY5Y cells. We then demonstrated binds BSG through facilitates cell surface. In neuroglial lines, silencing defects neuronal differentiation. Moreover, abrogation lactate transport SNX32-depleted cells led us propose may contribute maintaining coordination role associated monocarboxylate transporter activity. Taken together, our study showed mediates specific molecules along distinct pathways.

Language: Английский

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Transcorneal Electrical Stimulation Modulates Visual Pathway Function in Mice

Journal of Neuroscience Research, Journal Year: 2025, Volume and Issue: 103(2)

Published: Feb. 1, 2025

ABSTRACT Due to its ability modulate neuronal activity, electrical stimulation of the eye may be a promising therapy for preserving or restoring vision. To investigate how currents can influence visual function, Transcorneal Electrical Stimulation (TES) was tested on both female and male C57BL/6 mice evaluate neuromodulatory effect from retina cerebral cortex through evoked potential (VEP) electroretinogram (ERG) recording. VEP ERG acquired before (baseline), immediately (t0), after 5 min (t5), 10 (t10) sham (i.e., no stimulation) TES applied anesthetized mice. Notably, affected activity in pathway since significant increase amplitude detected persisted TES. The induced by could underlie an enhancement excitability that ameliorate retinal‐genicular‐cortical function diseases involving system.

Language: Английский

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Review: Utility of mass spectrometry in rare disease research and diagnosis

npj Genomic Medicine, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 31, 2025

Individuals affected by a rare disease often experience long and arduous diagnostic odyssey. Delivery of genetic answers in timely manner is critical to individuals their families. Multi-omics, term which usually encompasses genomics, transcriptomics, proteomics, metabolomics lipidomics, has gained increasing popularity research diagnosis over the past decade. Mass spectrometry (MS) technique allowing study proteins, metabolites lipids fragments at scale, enabling researchers effectively determine presence abundance thousands molecules single test, accurately quantify specific levels, identify potential therapeutic biomarkers, detect differentially expressed proteins patients with diseases, monitor progression treatment response. In this review, we focus on mass (MS)-based omics survey literature describing utility different MS-based how they have transformed diagnosis.

Language: Английский

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Characteristics of autosomal dominant WFS1-associated optic neuropathy and its comparability to OPA1-associated autosomal dominant optic atrophy

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Oct. 3, 2024

Language: Английский

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Longitudinal Imaging Biomarkers Correlate with Progressive Motor Deficit in the Mouse Model of Charlevoix‐Saguenay Ataxia

Annals of Neurology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 6, 2024

Objective In autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) disease, severity and age onset vary greatly, hindering to objectively measure predict clinical progression. Thickening the retinal nerve fiber layer is distinctive ARSACS patients, as assessed by optical coherence tomography, whereas conventional brain magnetic resonance imaging findings include both supratentorial infratentorial changes. Because longitudinal studies in patients are not available define these changes biomarkers disease progression, we aimed address this issue mouse model. Methods We performed OCT MRI Sacs −/− model, alongside motor coordination assessment beam walking test. also investigated visual function molecular mechanisms underlying RNFL increased thickness histology immunofluorescence. Results demonstrated that thickening gradually increases early stages pathology reflecting progression impairment, later reaches a plateau when thinning posterior corpus callosum becomes detectable MRI. Mechanistically, unveiled associated with aberrant accumulation non‐phosphorylated neurofilament H glial fibrillary acidic protein. uncovered mild signs myelin coherent latency evoked potentials, altered activation photopic electroretinography. Interpretation show may represent Our data gathers knowledge instrumental studies, holding potential readout for treatment efficacy. ANN NEUROL 2024

Language: Английский

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Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 13, 2023

Aim Wolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1 , with poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential pre-clinical clinical settings. Dual agonists that target GLP-1 glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated therapeutic of dual agonism loss-of-function rat model WS. Methods Eight-month-old knock-out (KO) wild-type control rats were continuously treated either agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity hearing sensitivity longitudinally monitored pre-treatment, then at 10.5 12 Pancreata retina harvested immunohistological analysis. Results therapy reversed glucose intolerance KO provided lasting anti-diabetogenic protection. Treatment also intra-islet alterations, including reduced endocrine islet area β-cell density, indicating its regenerative potential. Although rescue effect was noted loss, retinal ganglion cell density better preserved DA-CH5-treated rats. Conclusion We present preclinical evidence pleiotropic effects long-term treatment; seen despite treatment beginning after symptom-onset, reversal disease progression. incretins represent promising avenue WS patients.

Language: Английский

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

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 13, 2023

Wolfram syndrome (WS) is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect WS involves poor ER Ca²⁺ handling, but how this disturbance leads to not known. The current study, performed isolated neurons, most affected and disease-relevant cells, involving both genes, explains disturbed handling compromises mitochondrial function affects neuronal health. Loss of content axons WFS1- CISD2-deficient neurons associated with lower IP₃R-mediated transfer from mitochondria decreased uptake. In turn, reduction inhibits ATP production leading an increased axoplasmic NADH/NAD⁺ ratio. resulting bioenergetic deficit reductive stress compromise health neurons. Our work also identifies pharmacological targets compounds that restore homeostasis, enhance improve function.

Language: Английский

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