NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome

Crouzier, Lucie; Richard, E.; Diez, Camille; Denus, Morgane; Peyrel, Amandine; Alzaeem, Hala; Cubedo, Nicolas; Delaunay, Thomas; Maurice, Tangui; Delprat, Benjamin

doi:10.1016/j.omtm.2022.10.003

Cited by 9 publications

(12 citation statements)

References 66 publications

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“…Responsible for WS, variants of WFS1 were also associated with different forms of inherited deafness and Wolfram-like syndrome 42 . Despite the emergence of multiple animal models, none of them present with an early onset hearing loss, hampering the understanding of WFS1 role in the auditory pathway [25][26][27]43 .…”

Section: Discussionmentioning

confidence: 99%

“…However, all tested frequencies were affected for the mouse model while only low frequencies showed alterations in the Wfs1 de cient rat. Due to the late onset of the hearing impairment, it would be pertinent to evaluate or re-evaluate the audiology pro le of the other animal models, such as Wfs1 ΔExon2 mouse 28 or simple and double wfs1 zebra sh lines 26,27,43 . Unfortunately, no straightforward comparison can be made with the human pathology as no clear phenotype/genotype correlation can be established in affected individuals.…”

Section: Audiological Characterization Of the Wfs1mentioning

confidence: 99%

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Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

Richard

Brun

Korchagina

et al. 2023

Preprint

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Wolfram syndrome (WS) is a rare neurodegenerative disease encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) and neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1E864K line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, associated with a decrease of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na+/K+ATPase-β1 subunit, a key protein for the maintenance of the EP. Overall, our data support an important role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na+/K+ATPase β1-subunit.

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Section: Discussionmentioning

confidence: 99%

Section: Audiological Characterization Of the Wfs1mentioning

confidence: 99%

Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

Richard

Brun

Korchagina

et al. 2023

Preprint

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“…However, contrary to what was observed in WFS1 null fibroblasts, when the autophagy flux is blocked using BafA1, the relative rise of autophagosomes is less in the mutant than in the WT fibroblasts, suggesting an alteration of the autophagic machinery of these cells in basal conditions. A compromised autophagy is detrimental for neuronal cells, often time associated with neurodegeneration 29 , as reported not only in the pathophysiological context of WS 9,15 but also other neurodegenerative disorders 30 . The attenuated dysregulation of autophagy might explain why no degeneration has been reported so far in WLS patients 5 .…”

Section: Discussionmentioning

confidence: 93%

The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

Patergnani,

Bataillard,

Danese

et al. 2023

Preprint

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Dominant variants inWFS1, a gene coding for the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein Wolframin, have been associated with Wolfram-like syndrome (WLS).In vitroandin vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced autophagy and mitophagy. However, in WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that, in human fibroblasts and murine neuronal cultures, WLS protein WFS1E864Kleads to decreases in mitochondria bioenergetics and Ca2+uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in theWfs1E864Kmouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM’s integrity and functionality. It may open new treatment perspectives, until now non-existent, for patients with WLS.

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“…In zebrafish, IVT mRNA has been used for ectopic expression or overexpression experiments to study gene function after injection at the one-cell stage and modified IVT mRNA has been applied to manipulate the expression levels [ 10 ]. It is worth noting that zebrafish can tolerate mRNA sequences from other species, which can increase the cost-effectiveness of a project [ 11 , 12 , 13 ].…”

Section: In Vitro Transcribed (Ivt) Mrnamentioning

confidence: 99%

“…Wolframin protects NCS1, a Ca 2+ -sensor, from degradation and regulates the ER-mitochondria Ca 2+ transfer. Crouzier et al established a zebrafish model of Wolfram syndrome ( wfs1ab KO ) and demonstrated that the one-cell stage injection of murine Ncs1 mRNA can restore mitochondrial function and hyperlocomotion of the zebrafish [ 12 ]. Additionally, a zebrafish model of classic galactosemia (CG) ( galt KO ) , a hereditary disease of galactose metabolism caused by deficiency in galactose-1-phosphate:uridylyltransferase (GALT) activity, has been treated with human GALT mRNA by one-cell stage injection, resulting in enzyme activity and a decrease in the accumulated metabolites [ 11 ].…”

Section: Evaluating Mrna-based Therapies In the Zebrafishmentioning

confidence: 99%

The Zebrafish Embryo as a Model Organism for Testing mRNA-Based Therapeutics

Bondue

Berlingerio

Heuvel

et al. 2023

IJMS

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mRNA-based therapeutics have revolutionized the world of molecular therapy and have proven their potential in the vaccination campaigns for SARS-CoV2 and clinical trials for hereditary disorders. Preclinical studies have mainly focused on in vitro and rodent studies. However, research in rodents is costly and labour intensive, and requires ethical approval for all interventions. Zebrafish embryonic disease models are not always classified as laboratory animals and have been shown to be extremely valuable for high-throughput drug testing. Zebrafish larvae are characterized by their small size, optical transparency and high number of embryos, and are therefore also suited for the study of mRNA-based therapeutics. First, the one-cell stage injection of naked mRNA can be used to assess the effectivity of gene addition in vivo. Second, the intravascular injection in older larvae can be used to assess tissue targeting efficiency of (packaged) mRNA. In this review, we describe how zebrafish can be used as a steppingstone prior to testing mRNA in rodent models. We define the procedures that can be employed for both the one-cell stage and later-stage injections, as well as the appropriate procedures for post-injection follow-up.

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NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome

Cited by 9 publications

References 66 publications

Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

The Zebrafish Embryo as a Model Organism for Testing mRNA-Based Therapeutics

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NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome

Cited by 9 publications

References 66 publications

Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

The Wolfram-like variant WFS1E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

The Zebrafish Embryo as a Model Organism for Testing mRNA-Based Therapeutics

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The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice