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1. Wfs1 E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

Author

Elodie M. Richard, Emilie Brun, Julia Korchagina, Lucie Crouzier, Corentin Affortit, Stacy Alves, Chantal Cazevieille, Anne-Laure Mausset-Bonnefont, Marc Lenoir, Jean-Luc Puel, Tangui Maurice, Marc Thiry, Jing Wang, and Benjamin Delprat

Subjects
Cytology, QH573-671
Abstract

Abstract Wolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as 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 Wfs1 E864K line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, a collapse 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 a key role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na+/K+ATPase β1 subunit.

Published
2023
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2. Single-cell RNA-sequencing of stria vascularis cells in the adult Slc26a4 -/- mouse

Author

Jin-Young Koh, Corentin Affortit, Paul T. Ranum, Cody West, William D. Walls, Hidekane Yoshimura, Jian Q. Shao, Brian Mostaert, and Richard J.H. Smith

Subjects
Single-cell RNA sequencing, Stria vascularis cell, Spindle cells, Hearing loss, Slc26a4, Pendred syndrome, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background The primary pathological alterations of Pendred syndrome are endolymphatic pH acidification and luminal enlargement of the inner ear. However, the molecular contributions of specific cell types remain poorly characterized. Therefore, we aimed to identify pH regulators in pendrin-expressing cells that may contribute to the homeostasis of endolymph pH and define the cellular pathogenic mechanisms that contribute to the dysregulation of cochlear endolymph pH in Slc26a4 −/− mice. Methods We used single-cell RNA sequencing to identify both Slc26a4-expressing cells and Kcnj10-expressing cells in wild-type (WT, Slc26a4 +/+) and Slc26a4 −/− mice. Bioinformatic analysis of expression data confirmed marker genes defining the different cell types of the stria vascularis. In addition, specific findings were confirmed at the protein level by immunofluorescence. Results We found that spindle cells, which express pendrin, contain extrinsic cellular components, a factor that enables cell-to-cell communication. In addition, the gene expression profile informed the pH of the spindle cells. Compared to WT, the transcriptional profiles in Slc26a4 −/− mice showed downregulation of extracellular exosome-related genes in spindle cells. Immunofluorescence studies in spindle cells of Slc26a4 −/− mice validated the increased expression of the exosome-related protein, annexin A1, and the clathrin-mediated endocytosis-related protein, adaptor protein 2. Conclusion Overall, cell isolation of stria vascularis from WT and Slc26a4 −/− samples combined with cell type-specific transcriptomic analyses revealed pH-dependent alternations in spindle cells and intermediate cells, inspiring further studies into the dysfunctional role of stria vascularis cells in SLC26A4-related hearing loss.

Published
2023
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3. Exacerbated age-related hearing loss in mice lacking the p43 mitochondrial T3 receptor

Author

Corentin Affortit, François Casas, Sabine Ladrech, Jean-Charles Ceccato, Jérôme Bourien, Carolanne Coyat, Jean-Luc Puel, Marc Lenoir, and Jing Wang

Subjects
Age-related hearing loss, Thyroid hormones, p43 mitochondrial T3 receptor, Mitochondrial dysfunction, Biology (General), QH301-705.5
Abstract

Abstract Background Age-related hearing loss (ARHL), also known as presbycusis, is the most common sensory impairment seen in elderly people. However, the cochlear aging process does not affect people uniformly, suggesting that both genetic and environmental (e.g., noise, ototoxic drugs) factors and their interaction may influence the onset and severity of ARHL. Considering the potential links between thyroid hormone, mitochondrial activity, and hearing, here, we probed the role of p43, a N-terminally truncated and ligand-binding form of the nuclear receptor TRα1, in hearing function and in the maintenance of hearing during aging in p43−/− mice through complementary approaches, including in vivo electrophysiological recording, ultrastructural assessments, biochemistry, and molecular biology. Results We found that the p43−/− mice exhibit no obvious hearing loss in juvenile stages, but that these mice developed a premature, and more severe, ARHL resulting from the loss of cochlear sensory outer and inner hair cells and degeneration of spiral ganglion neurons. Exacerbated ARHL in p43−/− mice was associated with the early occurrence of a drastic fall of SIRT1 expression, together with an imbalance between pro-apoptotic Bax, p53 expression, and anti-apoptotic Bcl2 expression, as well as an increase in mitochondrial dysfunction, oxidative stress, and inflammatory process. Finally, p43−/− mice were also more vulnerable to noise-induced hearing loss. Conclusions These results demonstrate for the first time a requirement for p43 in the maintenance of hearing during aging and highlight the need to probe the potential link between human THRA gene polymorphisms and/or mutations and accelerated age-related deafness or some adult-onset syndromic deafness.

Published
2021
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4. A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

Author

Fabian Blanc, Alexis-Pierre Bemelmans, Corentin Affortit, Charlène Joséphine, Jean-Luc Puel, Michel Mondain, and Jing Wang

Subjects
cisterna magna injection, AAV, cochlea, binaural gene transduction, hearing, Biology (General), QH301-705.5
Abstract

Viral-mediated gene augmentation, silencing, or editing offers tremendous promise for the treatment of inherited and acquired deafness. Inner-ear gene therapies often require a safe, clinically useable and effective route of administration to target both ears, while avoiding damage to the delicate structures of the inner ear. Here, we examined the possibility of using a cisterna magna injection as a new cochlear local route for initiating binaural transduction by different serotypes of the adeno-associated virus (AAV2/8, AAV2/9, AAV2/Anc80L65). The results were compared with those following canalostomy injection, one of the existing standard inner ear local delivery routes. Our results demonstrated that a single injection of AAVs enables high-efficiency binaural transduction of almost all inner hair cells with a basal-apical pattern and of large numbers of spiral ganglion neurons of the basal portion of the cochlea, without affecting auditory function and cochlear structures. Taken together, these results reveal the potential for using a cisterna magna injection as a local route for binaural gene therapy applications, but extensive testing will be required before translation beyond mouse models.

Published
2022
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5. Impulse Noise Induced Hidden Hearing Loss, Hair Cell Ciliary Changes and Oxidative Stress in Mice

Author

Paul Gratias, Jamal Nasr, Corentin Affortit, Jean-Charles Ceccato, Florence François, François Casas, Rémy Pujol, Sylvie Pucheu, Jean-Luc Puel, and Jing Wang

Subjects
impulse noise, oxidative stress, hidden hearing loss, cochlea, Therapeutics. Pharmacology, RM1-950
Abstract

Recent studies demonstrated that reversible continuous noise exposure may induce a temporary threshold shift (TTS) with a permanent degeneration of auditory nerve fibers, although hair cells remain intact. To probe the impact of TTS-inducing impulse noise exposure on hearing, CBA/J Mice were exposed to noise impulses with peak pressures of 145 dB SPL. We found that 30 min after exposure, the noise caused a mean elevation of ABR thresholds of ~30 dB and a reduction in DPOAE amplitude. Four weeks later, ABR thresholds and DPOAE amplitude were back to normal in the higher frequency region (8–32 kHz). At lower frequencies, a small degree of PTS remained. Morphological evaluations revealed a disturbance of the stereociliary bundle of outer hair cells, mainly located in the apical regions. On the other hand, the reduced suprathreshold ABR amplitudes remained until 4 weeks later. A loss of synapse numbers was observed 24 h after exposure, with full recovery two weeks later. Transmission electron microscopy revealed morphological changes at the ribbon synapses by two weeks post exposure. In addition, increased levels of oxidative stress were observed immediately after exposure, and maintained for a further 2 weeks. These results clarify the pathology underlying impulse noise-induced sensory dysfunction, and suggest possible links between impulse-noise injury, cochlear cell morphology, metabolic changes, and hidden hearing loss.

Published
2021
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6. Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production

Author

Elodie Richard, Emilie Brun, Julia Korchagina, Lucie Crouzier, Corentin Affortit, Stacy Alves, Chantal Cazevieille, Anne-Laure Bonnefont-Mausset, Marc Lenoir, jean-luc Puel, TANGUI MAURICE, Marc Thiry, jing wang, and Benjamin Delprat

Abstract

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.

Published
2023
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7. Influence of Matrix Metalloproteinases content on eardrum atrophy in Otitis Media with Effusion in children

Author

Lylou Casteil, Corentin Affortit, Jean Luc Puel, Fabian Blanc, Frederic Venail, Jing Wang, and Michel Mondain

Abstract

Objectives Otitis media with effusion (OME) is a common pathology in children. Effusions contain Metalloproteinases (MMPs), which can lead to atrophy of the tympanic membrane (TM) due to destructive effect on the lamina propria. Not all cases of OME are complicated with atrophy, maybe explained by an inter-individual variation of MMP concentration in effusions. The purpose of this study was to determine the correlation between concentration of MMPs and existence of TM atrophy in children. Participants - Main outcome measures The effusion from thirty middle ears were collected during insertion of VT in children aged 15 months to 10 years, including 11 eardrums with tympanic atrophy and 19 without tympanic atrophy. ELISA tests were used to measure concentrations of MMP-2, MMP-7, MMP-9 and TIMP-2 in the effusions. Correlations between MMP levels and atrophy of eardrum was investigated, as well as correlation with age, gender, number of previous ventilation tube insertion, and viscosity of the glue. Results The mean concentration of MMP-2 was higher in the atrophic group than in effusions without TM atrophy (0.6 ng/mg versus 0.5 ng/mg total protein respectively), while the TIMP-2 concentration was lower in this group. The level of MMP-2 decreased with the age. Finally, a significantly higher concentration of MMP-9 and TIMP-2 was found in high-viscosity effusions. Conclusion This study suggests that MMP-2 activity could play an important role in destruction of the eardrum during OME in infancy. MMP-2 level assessment could be interesting for determining children with risk of lamina propria destruction.

Published
2022
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8. Impulse Noise Induced Hidden Hearing Loss, Hair Cell Ciliary Changes and Oxidative Stress in Mice

Author

J C Ceccato, Jean-Luc Puel, Corentin Affortit, Sylvie Pucheu, Jing Wang, François Casas, Florence François, Paul Gratias, Jamal Nasr, Rémy Pujol, Raynaud, Christelle, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Cilcare, and Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM)

Subjects
medicine.medical_specialty, Physiology, Hearing loss, [SDV]Life Sciences [q-bio], Clinical Biochemistry, cochlea, RM1-950, Ribbon synapse, Audiology, Cell morphology, Impulse noise, Biochemistry, Article, Synapse, 03 medical and health sciences, 0302 clinical medicine, medicine, otorhinolaryngologic diseases, oxidative stress, Molecular Biology, Cochlea, impulse noise, hidden hearing loss, 030304 developmental biology, 0303 health sciences, business.industry, Cell Biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hair cell, sense organs, Therapeutics. Pharmacology, medicine.symptom, business, Auditory fatigue, 030217 neurology & neurosurgery
Abstract

International audience; Recent studies demonstrated that reversible continuous noise exposure may induce a temporary threshold shift (TTS) with a permanent degeneration of auditory nerve fibers, although hair cells remain intact. To probe the impact of TTS-inducing impulse noise exposure on hearing, CBA/J Mice were exposed to noise impulses with peak pressures of 145 dB SPL. We found that 30 min after exposure, the noise caused a mean elevation of ABR thresholds of ~30 dB and a reduction in DPOAE amplitude. Four weeks later, ABR thresholds and DPOAE amplitude were back to normal in the higher frequency region (8–32 kHz). At lower frequencies, a small degree of PTS remained. Morphological evaluations revealed a disturbance of the stereociliary bundle of outer hair cells, mainly located in the apical regions. On the other hand, the reduced suprathreshold ABR amplitudes remained until 4 weeks later. A loss of synapse numbers was observed 24 h after exposure, with full recovery two weeks later. Transmission electron microscopy revealed morphological changes at the ribbon synapses by two weeks post exposure. In addition, increased levels of oxidative stress were observed immediately after exposure, and maintained for a further 2 weeks. These results clarify the pathology underlying impulse noise-induced sensory dysfunction, and suggest possible links between impulse-noise injury, cochlear cell morphology, metabolic changes, and hidden hearing loss.

Published
2021
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9. ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

Author

Jean-Luc Puel, Nesrine Benkafadar, Jean Charles Ceccato, Frédéric Venail, Florence François, Julien Menardo, Bernard Malfroy-Camine, Jing Wang, Corentin Affortit, François Casas, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), MindSet, ProdInra, Archive Ouverte, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), and Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, DNA Repair, [SDV]Life Sciences [q-bio], Cell, Apoptosis, medicine.disease_cause, Mice, 0302 clinical medicine, Hearing, Cellular Senescence, chemistry.chemical_classification, biology, Cell biology, Cochlea, Up-Regulation, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Phenotype, Neurology, Hair cell, medicine.symptom, DNA damage responses, Hearing preservation, Senescence, Age-related hearing loss, DNA damage, Hearing loss, Neuroscience (miscellaneous), Mitosis, Article, Superoxide dismutase, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, otorhinolaryngologic diseases, Autophagy, Organometallic Compounds, Animals, Hearing Loss, Reactive oxygen species, Antioxidant Response Elements, Oxidative Stress, 030104 developmental biology, chemistry, biology.protein, Reactive Oxygen Species, 030217 neurology & neurosurgery, Oxidative stress, DNA Damage
Abstract

In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS) may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNA damage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our results revealed that sublethal concentrations of hydrogen peroxide (H2O2) exposure initiated a DNA damage response illustrated by increased γH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H2O2 displayed key hallmarks of senescent cells, including dramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression and positive senescence-associated β-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H2O2-induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic administration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8 (SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentially postpone cochlear aging and prevent ARHL in humans.

Published
2019
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10. rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application

Author

Jing Wang, Fabian Blanc, Corentin Affortit, Michel Mondain, Jean-Luc Puel, Alexis-Pierre Bemelmans, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Institut des Neurosciences de Montpellier (INM), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and ANR-10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010)

Subjects
routes of delivery, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Hearing loss, Genetic enhancement, viruses, Systemic injection, lcsh:Medicine, Review, Bioinformatics, Genome, 03 medical and health sciences, 0302 clinical medicine, Genome editing, RNA interference, genetic deafness, otorhinolaryngologic diseases, Medicine, In patient, Gene, targets gene addition, 030304 developmental biology, 0303 health sciences, business.industry, gene editing, [SCCO.NEUR]Cognitive science/Neuroscience, lcsh:R, General Medicine, raav, rnai, 3. Good health, cochlear gene therapy, clinical application, serotypes, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

International audience; Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.

Published
2020
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11. ER-mitochondria cross-talk is regulated by the Ca 2+ sensor NCS1 and is impaired in Wolfram syndrome

Author

Jennifer Rieusset, Benjamin Delprat, Dan Milea, Chantal Cazevieille, Mélanie Quiles, Marc Thiry, Paolo Pinton, Julia Korchagina, Claire Angebault, Alberto Danese, Camille Mégy, Delphine Bonnet-Wersinger, Simone Patergnani, Alain Lacampagne, Corentin Affortit, Christian P. Hamel, Jolanta Jagodzinska, Jérémy Fauconnier, Cécile Delettre, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Ferrara (UniFE), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Service d'ophtalmologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Singapore Eye Research Institute [Singapore] (SERI), Centre de référence pour les maladies génétiques sensorielles [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], Université de Liège-C.H.U. Sart Tilman [Liège], Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), We are indebted to the INSERM and Université Montpellier for providing institutional support and to the patient associations Union National des Aveugles et Déficients Visuels (UNADEV) and Association Syndrome de Wolfram for their financial support. This work was supported by grants from the Agence Nationale pour la Recherche (ANR-12-JSV1-0008-01), Fondation pour la Recherche Médicale, and Fondation de France. C.A. was supported by the Fondation de France., ANR-12-JSV1-0001,LIPIDOPAIN,Implication des métabolites des acide gars polyinsaturés et des récepteurs canaux 'TRP' dans l'hypersensibilité viscérale(2012), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Ferrara [Ferrara], Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), ANR-12-JSV1-0001,LIPIDOPAIN,Implication des métabolites des acide gars polyinsaturés et des récepteurs canaux TRP dans l'hypersensibilité viscérale(2012), Institut des Neurosciences de Montpellier (INM), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Delprat, Benjamin, and Jeunes Chercheuses et Jeunes Chercheurs - Implication des métabolites des acide gars polyinsaturés et des récepteurs canaux 'TRP' dans l'hypersensibilité viscérale - - LIPIDOPAIN2012 - ANR-12-JSV1-0001 - JC - VALID

Subjects
0301 basic medicine, endocrine system diseases, Wolfram syndrome, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, Biochemistry, NO, stress, 03 medical and health sciences, chemistry.chemical_compound, neurodegenaration, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Inositol, Receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, endoplasmic reticulum membranes, Biochemistry, Molecular Biology, Cell Biology, endoplasmic reticulum membranes, mitfusin 2, protein, neurodegenaration, activation, transport, stress, biology, Chemistry, Endoplasmic reticulum, HEK 293 cells, Cell Biology, medicine.disease, mitfusin 2, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Neuronal calcium sensor-1, transport, biology.protein, activation, Signal transduction, protein
Abstract

International audience; Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca2+ signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IP3R) to promote Ca2+ transfer between the ER and mitochondria. In addition, we found that NCS1 abundance was reduced in WFS1-null patient fibroblasts, which showed reduced ER-mitochondria interactions and Ca2+ exchange. Moreover, in WFS1-deficient cells, NCS1 overexpression not only restored ER-mitochondria interactions and Ca2+ transfer but also rescued mitochondrial dysfunction. Our results describe a key role of NCS1 in ER-mitochondria cross-talk, uncover a pathogenic mechanism for Wolfram syndrome, and potentially reveal insights into the pathogenesis of other neurodegenerative diseases.

Published
2018
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