The Experts below are selected from a list of 147 Experts worldwide ranked by ideXlab platform

Pascale Bomont - One of the best experts on this subject based on the ideXlab platform.

  • Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production.
    Nature communications, 2019
    Co-Authors: Aurora Scrivo, Patrice Codogno, Pascale Bomont
    Abstract:

    Autophagy is an essential self-digestion machinery for cell survival and homoeostasis. Membrane elongation is fundamental, as it drives the formation of the double-membrane vesicles that engulf cytosolic material. LC3-lipidation, the signature of autophagosome formation, results from a complex ubiquitin-conjugating cascade orchestrated by the ATG16L1 protein, whose regulation is unknown. Here, we identify the Gigaxonin-E3 ligase as the first regulator of ATG16L1 turn-over and autophagosome production. Gigaxonin interacts with the WD40 domain of ATG16L1 to drive its ubiquitination and subsequent degradation. Gigaxonin depletion induces the formation of ATG16L1 aggregates and impairs LC3 lipidation, hence altering lysosomal fusion and degradation of the main autophagy receptor p62. Altogether, we demonstrate that the Gigaxonin-E3 ligase controls the production of autophagosomes by a reversible, ubiquitin-dependent process selective for ATG16L1. Our findings unveil the fundamental mechanisms of the control of autophagosome formation, and provide a molecular switch to fine-tune the activation of autophagy. Membrane elongation is fundamental to autophagy and is controlled by an ubiquitin-conjugating cascade orchestrated by ATG16L1. Here, the authors identify that the E3 ligase Gigaxonin regulates autophagosome formation by controlling ATG16L1 turnover.

  • Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production
    Nature Publishing Group, 2019
    Co-Authors: Aurora Scrivo, Patrice Codogno, Pascale Bomont
    Abstract:

    Membrane elongation is fundamental to autophagy and is controlled by an ubiquitin-conjugating cascade orchestrated by ATG16L1. Here, the authors identify that the E3 ligase Gigaxonin regulates autophagosome formation by controlling ATG16L1 turnover

  • giant axonal neuropathy associated Gigaxonin mutations impair intermediate filament protein degradation
    Journal of Clinical Investigation, 2013
    Co-Authors: Saleemulla Mahammad, Pascale Bomont, S Prasanna N Murthy, Alessandro Didonna, Boris Grin, Eitan Israeli, Rodolphe Perrot, Jeanpierre Julien, Edward R Kuczmarski, Puneet Opal
    Abstract:

    Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for Gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients’ dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan–/– mice, we demonstrated that Gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing Gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify Gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.

  • Gigaxonin controls vimentin organization through a tubulin chaperone-independent pathway
    Human molecular genetics, 2009
    Co-Authors: Don W. Cleveland, Koji Yamanaka, Pascale Bomont
    Abstract:

    Gigaxonin mutations cause the fatal human neurodegenerative disorder giant axonal neuropathy (GAN). Broad deterioration of the nervous system in GAN patients is accompanied by massive disorganization of intermediate filaments (IFs) both in neurons and many non-neuronal cells. With newly developed antibodies, Gigaxonin is now shown to be expressed at extremely low levels throughout the nervous system. In lymphoblast cell lines derived from severe and mild forms of GAN, mutations in Gigaxonin are shown to yield highly unstable proteins, thereby permitting a rapid diagnostic test for the spectrum of GAN mutations as an alternative to invasive nerve biopsy or systematic sequencing of the GAN gene. Gigaxonin has been proposed as a substrate adaptor for an E3 ubiquitin ligase, which affects proteasome-dependent degradation of microtubule-related proteins including MAP1B, MAP8 and the tubulin folding chaperone TBCB. We demonstrate that, unlike its counterpart TBCE, TBCB only moderately destabilizes microtubules. Neither TBCB abundance nor microtubule organization or densities are altered in GAN mutant fibroblasts, thus demonstrating that altered TBCB levels are not primary determinants of IF disorganization in GAN. Characteristic GAN mutant-induced ovoid aggregates of vimentin are not produced in normal fibroblasts after disrupting microtubule assembly, either by TBCE overexpression or depolymerizing drugs. Thus, IF disorganization in GAN fibroblasts is independent of TBCB and microtubule loss and must be regulated by a yet unidentified mechanism.

  • the gene encoding Gigaxonin a new member of the cytoskeletal btb kelch repeat family is mutated in giant axonal neuropathy
    Nature Genetics, 2000
    Co-Authors: Pascale Bomont, Laurent Cavalier, François Blondeau, Christiane Ben Hamida, Samir Belal, Meriem Tazir, Ercan Demir, Haluk Topaloglu, Rudolf Korinthenberg, Beyhan Tüysüz
    Abstract:

    Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named Gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a beta-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that Gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.

Bomont Pascale - One of the best experts on this subject based on the ideXlab platform.

  • Sonic Hedgehog repression underlies Gigaxonin mutation–induced motor deficits in giant axonal neuropathy
    American Society for Clinical Investigation, 2019
    Co-Authors: Arribat Yoan, Mysiak Karolina, Lescouzères Léa, Boizot Alexia, Ruiz Maxime, Rossel Mireille, Bomont Pascale
    Abstract:

    International audienceGrowing evidence shows that alterations occurring at early developmental stages contribute to symptoms manifested in adulthood in the setting of neurodegenerative diseases. Here, we studied the molecular mechanisms causing giant axonal neuropathy (GAN), a severe neurodegenerative disease due to loss-of-function of the Gigaxonin-E3 ligase. We showed that Gigaxonin governs Sonic Hedgehog (Shh) induction, the developmental pathway patterning the dorso-ventral axis of the neural tube and muscles, by controlling the degradation of the Shh-bound Patched receptor. Similar to Shh inhibition, repression of Gigaxonin in zebrafish impaired motor neuron specification and somitogenesis and abolished neuromuscular junction formation and locomotion. Shh signaling was impaired in Gigaxonin-null zebrafish and was corrected by both pharmacological activation of the Shh pathway and human Gigaxonin, pointing to an evolutionary-conserved mechanism regulating Shh signaling. Gigaxonin-dependent inhibition of Shh activation was also demonstrated in primary fibroblasts from patients with GAN and in a Shh activity reporter line depleted in Gigaxonin. Our findings establish Gigaxonin as a key E3 ligase that positively controls the initiation of Shh transduction, and reveal the causal role of Shh dysfunction in motor deficits, thus highlighting the developmental origin of GAN

  • Giant axonal neuropathy–associated Gigaxonin mutations impair intermediate filament protein degradation
    'American Society for Clinical Investigation', 2013
    Co-Authors: Mahammad Saleemulla, Bomont Pascale, Prasanna Murthy S. N., Didonna Alessandro, Grin Boris, Israeli Eitan, Perrot Rodolphe, Julien Jean-pierre, Kuczmarski Edward, Opal Puneet
    Abstract:

    Author Posting. © American Society for Clinical Investigation, 2013. This article is posted here by permission of American Society for Clinical Investigation for personal use, not for redistribution. The definitive version was published in Journal of Clinical Investigation 123 (2013): 1964–1975, doi:10.1172/JCI66387.Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for Gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients’ dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan–/– mice, we demonstrated that Gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing Gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify Gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.This work was supported by NIH grants 1P01GM096971 (to R.D. Goldman) and R01 NS062051 (to P. Opal) and a grant from Hannah’s Hope Fund (to R.D. Goldman and P. Opal)

  • Sensory-motor deficits and neurofilament disorganization in Gigaxonin-null mice
    BMC, 2011
    Co-Authors: Boizot Alexia, Ganay Thibault, Burrer Renaud, Chauvin Jean, Bomont Pascale
    Abstract:

    Abstract Background Giant Axonal Neuropathy (GAN) is a fatal neurodegenerative disorder with early onset characterized by a severe deterioration of the peripheral and central nervous system, involving both the motor and the sensory tracts and leading to ataxia, speech defect and intellectual disabilities. The broad deterioration of the nervous system is accompanied by a generalized disorganization of the intermediate filaments, including neurofilaments in neurons, but the implication of this defect in disease onset or progression remains unknown. The identification of Gigaxonin, the substrate adaptor of an E3 ubiquitin ligase, as the defective protein in GAN allows us to now investigate the crucial role of the Gigaxonin-E3 ligase in sustaining neuronal and intermediate filament integrity. To study the mechanisms controlled by Gigaxonin in these processes and to provide a relevant model to test the therapeutic approaches under development for GAN, we generated a Gigaxonin-null mouse by gene targeting. Results We investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that Gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another Gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology. Conclusions Together, our results show that Gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the severe neurofilament dysregulation seen in patients. Our model will allow investigation of the role of the Gigaxonin-E3 ligase in organizing neurofilaments and may prove useful in understanding the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of neurofilaments and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases.

  • Sensory-motor deficits and Neurofilament disorganization in Gigaxonin-null mice.
    'Springer Science and Business Media LLC', 2011
    Co-Authors: Ganay Thibault, Boizot Alexia, Burrer Renaud, Chauvin Jean, Bomont Pascale
    Abstract:

    International audienceABSTRACT: BACKGROUND: Giant Axonal Neuropathy (GAN) is a fatal neurodegenerative disorder with early onset characterized by a severe deterioration of the peripheral and central nervous system, involving both the motor and sensory tracts and leading to ataxia, speech defect and intellectual disabilities. The broad deterioration of the nervous system is accompanied by a generalized disorganization of the intermediate filaments, including neurofilaments in neurons, but the implication of this defect in disease onset or progression remains unknown. The identification of Gigaxonin, the substrate adaptor of an E3 ubiquitin ligase, as the defective protein in GAN allows us to now investigate the crucial role of the Gigaxonin-E3 ligase in sustaining neuronal and intermediate filament integrity. To study the mechanisms controlled by Gigaxonin in these processes and to provide a relevant model to test the therapeutic approaches under development for GAN, we generated a Gigaxonin-null mouse by gene targeting. RESULTS: We investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that Gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another Gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology. CONCLUSIONS: Together, our results show that Gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the severe neurofilament dysregulation seen in patients. Our model will allow investigation of the role of the Gigaxonin-E3 ligase in organizing neurofilaments and may prove useful in understanding the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of neurofilaments and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases

  • Caractérisation du modèle murin de la Neuropathie à Axones Géants (rôle de la Gigaxonine dans la survie neuronale et l'organisation du cytosquelette)
    2011
    Co-Authors: Ganay Thibault, Bomont Pascale
    Abstract:

    La Neuropathie à Axones Géants (NAG) est une maladie neurodégénérative rare et fatale caractérisée par une détérioration du système nerveux central et périphérique, impliquant les fonctions motrices et sensorielles. La détérioration massive du système nerveux est accompagnée d'une désorganisation générale des Filaments Intermédiaires ce qui la différencie de nombreuses maladies neurodégénératives où seuls les neurofilaments(NFs) sont affectés. La protéine déficiente, la Gigaxonine, est la sous-unité d'une ubiquitine ligase E3, responsable de la reconnaissance spécifique des substrats MAP1B, MAP1S et TBCB, seuls connus à ce jour.Dans le but d'étudier le rôle de la Gigaxonine sur la survie neuronale, la désorganisation du cytosquelette et d'avoir un modèle animal suffisamment fort pour envisager des tests thérapeutiques, j'ai caractérisé un modèle murin de NAG. Pour ce faire, j'ai réalisé une étude comportementale des fonctions motrices et sensorielles ainsi qu'une étude histopathologique. Les souris NAG (129/SvJ) développent un phénotype moteur modéré dès 60 semaines alors que les souris NAG (C57BL/6) présentent un phénotype sensoriel dès 60 semaines. Les données histopathologiques ne présentent pas de mort neuronale mais les NFs sont sévèrement altérés. Les NFs sont plus abondant, leur diamètre est augmenté et leur orientation hétérogène, comme c'est observé chez les patients NAG.Nos résultats montrent que l'absence de Gigaxonine induit un phénotype moteur et sensoriel modéré mais par contre reproduit la désorganisation massive des NFs observée chez les patients. Ce modèle va nous permettred'étudier le rôle de la Gigaxonine, une ligase E3, sur l'organisation des NFs et ainsi comprendre les processus pathologiques impliqués dans d'autres maladies neurodégénératives caractérisée par une accumulation des NFs et un dysfonctionnement du système ubiquitine-protéasome comme les maladies d'Azheimer, de Parkinson etd'huntington ou la sclérose latérale amyotrophique.Giant Axonal Neuropathy (GAN) is a rare and fatale neurodegenerative disorder characterized by a deterioration of the peripheral and central nervous system. The broad deterioration of the nervous system is accompanied with a general disorganization of the Intermediate Filaments which makes it different from other neurodegenerative disorders wherein only neurofilaments (NFs) are affected. The defective protein, Gigaxonin, is the substrate adaptator of an E3 ubiquitin ligase, in charge of the specific recognition of MAP1B, MAP1S and TBCB. In order to study the role of Gigaxonin on neuronal survival, the cytoskeleton disorganization and to have a relevant GAN animal model to evaluate efficacy of GAN treatments, I have characterized a GAN mouse model. I did a motor and sensory behavioural study and an histopathologic study. The GAN mice (129/SvJ) shown mild motordeficits starting at 60 weeks of age while sensory deficits were evidenced in C57BL/6 GAN mice. No apparent neurodegeneration was evidenced in GAN mice, but dysregulation of NFs was massive. NFs were more abundant, they shown the abnormal increased diameter and misorientation that are characteristics of the human pathology. Our results show that Gigaxonin depletion induces mild motor and sensory deficits but recapitulates the severe NFs dysregulation seen in patients. Our model will allow us to study the role of the Gigaxonin-E3 ligase in organizing NFs and understand the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of NFs and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases.AIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

Ganay Thibault - One of the best experts on this subject based on the ideXlab platform.

  • Sensory-motor deficits and neurofilament disorganization in Gigaxonin-null mice
    BMC, 2011
    Co-Authors: Boizot Alexia, Ganay Thibault, Burrer Renaud, Chauvin Jean, Bomont Pascale
    Abstract:

    Abstract Background Giant Axonal Neuropathy (GAN) is a fatal neurodegenerative disorder with early onset characterized by a severe deterioration of the peripheral and central nervous system, involving both the motor and the sensory tracts and leading to ataxia, speech defect and intellectual disabilities. The broad deterioration of the nervous system is accompanied by a generalized disorganization of the intermediate filaments, including neurofilaments in neurons, but the implication of this defect in disease onset or progression remains unknown. The identification of Gigaxonin, the substrate adaptor of an E3 ubiquitin ligase, as the defective protein in GAN allows us to now investigate the crucial role of the Gigaxonin-E3 ligase in sustaining neuronal and intermediate filament integrity. To study the mechanisms controlled by Gigaxonin in these processes and to provide a relevant model to test the therapeutic approaches under development for GAN, we generated a Gigaxonin-null mouse by gene targeting. Results We investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that Gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another Gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology. Conclusions Together, our results show that Gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the severe neurofilament dysregulation seen in patients. Our model will allow investigation of the role of the Gigaxonin-E3 ligase in organizing neurofilaments and may prove useful in understanding the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of neurofilaments and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases.

  • Sensory-motor deficits and Neurofilament disorganization in Gigaxonin-null mice.
    'Springer Science and Business Media LLC', 2011
    Co-Authors: Ganay Thibault, Boizot Alexia, Burrer Renaud, Chauvin Jean, Bomont Pascale
    Abstract:

    International audienceABSTRACT: BACKGROUND: Giant Axonal Neuropathy (GAN) is a fatal neurodegenerative disorder with early onset characterized by a severe deterioration of the peripheral and central nervous system, involving both the motor and sensory tracts and leading to ataxia, speech defect and intellectual disabilities. The broad deterioration of the nervous system is accompanied by a generalized disorganization of the intermediate filaments, including neurofilaments in neurons, but the implication of this defect in disease onset or progression remains unknown. The identification of Gigaxonin, the substrate adaptor of an E3 ubiquitin ligase, as the defective protein in GAN allows us to now investigate the crucial role of the Gigaxonin-E3 ligase in sustaining neuronal and intermediate filament integrity. To study the mechanisms controlled by Gigaxonin in these processes and to provide a relevant model to test the therapeutic approaches under development for GAN, we generated a Gigaxonin-null mouse by gene targeting. RESULTS: We investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that Gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another Gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology. CONCLUSIONS: Together, our results show that Gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the severe neurofilament dysregulation seen in patients. Our model will allow investigation of the role of the Gigaxonin-E3 ligase in organizing neurofilaments and may prove useful in understanding the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of neurofilaments and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases

  • Caractérisation du modèle murin de la Neuropathie à Axones Géants (rôle de la Gigaxonine dans la survie neuronale et l'organisation du cytosquelette)
    2011
    Co-Authors: Ganay Thibault, Bomont Pascale
    Abstract:

    La Neuropathie à Axones Géants (NAG) est une maladie neurodégénérative rare et fatale caractérisée par une détérioration du système nerveux central et périphérique, impliquant les fonctions motrices et sensorielles. La détérioration massive du système nerveux est accompagnée d'une désorganisation générale des Filaments Intermédiaires ce qui la différencie de nombreuses maladies neurodégénératives où seuls les neurofilaments(NFs) sont affectés. La protéine déficiente, la Gigaxonine, est la sous-unité d'une ubiquitine ligase E3, responsable de la reconnaissance spécifique des substrats MAP1B, MAP1S et TBCB, seuls connus à ce jour.Dans le but d'étudier le rôle de la Gigaxonine sur la survie neuronale, la désorganisation du cytosquelette et d'avoir un modèle animal suffisamment fort pour envisager des tests thérapeutiques, j'ai caractérisé un modèle murin de NAG. Pour ce faire, j'ai réalisé une étude comportementale des fonctions motrices et sensorielles ainsi qu'une étude histopathologique. Les souris NAG (129/SvJ) développent un phénotype moteur modéré dès 60 semaines alors que les souris NAG (C57BL/6) présentent un phénotype sensoriel dès 60 semaines. Les données histopathologiques ne présentent pas de mort neuronale mais les NFs sont sévèrement altérés. Les NFs sont plus abondant, leur diamètre est augmenté et leur orientation hétérogène, comme c'est observé chez les patients NAG.Nos résultats montrent que l'absence de Gigaxonine induit un phénotype moteur et sensoriel modéré mais par contre reproduit la désorganisation massive des NFs observée chez les patients. Ce modèle va nous permettred'étudier le rôle de la Gigaxonine, une ligase E3, sur l'organisation des NFs et ainsi comprendre les processus pathologiques impliqués dans d'autres maladies neurodégénératives caractérisée par une accumulation des NFs et un dysfonctionnement du système ubiquitine-protéasome comme les maladies d'Azheimer, de Parkinson etd'huntington ou la sclérose latérale amyotrophique.Giant Axonal Neuropathy (GAN) is a rare and fatale neurodegenerative disorder characterized by a deterioration of the peripheral and central nervous system. The broad deterioration of the nervous system is accompanied with a general disorganization of the Intermediate Filaments which makes it different from other neurodegenerative disorders wherein only neurofilaments (NFs) are affected. The defective protein, Gigaxonin, is the substrate adaptator of an E3 ubiquitin ligase, in charge of the specific recognition of MAP1B, MAP1S and TBCB. In order to study the role of Gigaxonin on neuronal survival, the cytoskeleton disorganization and to have a relevant GAN animal model to evaluate efficacy of GAN treatments, I have characterized a GAN mouse model. I did a motor and sensory behavioural study and an histopathologic study. The GAN mice (129/SvJ) shown mild motordeficits starting at 60 weeks of age while sensory deficits were evidenced in C57BL/6 GAN mice. No apparent neurodegeneration was evidenced in GAN mice, but dysregulation of NFs was massive. NFs were more abundant, they shown the abnormal increased diameter and misorientation that are characteristics of the human pathology. Our results show that Gigaxonin depletion induces mild motor and sensory deficits but recapitulates the severe NFs dysregulation seen in patients. Our model will allow us to study the role of the Gigaxonin-E3 ligase in organizing NFs and understand the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of NFs and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases.AIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

  • Caractérisation du modèle murin de la Neuropathie à Axones Géants : rôle de la Gigaxonine dans la survie neuronale et l'organisation du cytosquelette
    2011
    Co-Authors: Ganay Thibault
    Abstract:

    La Neuropathie à Axones Géants (NAG) est une maladie neurodégénérative rare et fatale caractérisée par une détérioration du système nerveux central et périphérique, impliquant les fonctions motrices et sensorielles. La détérioration massive du système nerveux est accompagnée d'une désorganisation générale des Filaments Intermédiaires ce qui la différencie de nombreuses maladies neurodégénératives où seuls les neurofilaments(NFs) sont affectés. La protéine déficiente, la Gigaxonine, est la sous-unité d'une ubiquitine ligase E3, responsable de la reconnaissance spécifique des substrats MAP1B, MAP1S et TBCB, seuls connus à ce jour.Dans le but d'étudier le rôle de la Gigaxonine sur la survie neuronale, la désorganisation du cytosquelette et d'avoir un modèle animal suffisamment fort pour envisager des tests thérapeutiques, j'ai caractérisé un modèle murin de NAG. Pour ce faire, j'ai réalisé une étude comportementale des fonctions motrices et sensorielles ainsi qu'une étude histopathologique. Les souris NAG (129/SvJ) développent un phénotype moteur modéré dès 60 semaines alors que les souris NAG (C57BL/6) présentent un phénotype sensoriel dès 60 semaines. Les données histopathologiques ne présentent pas de mort neuronale mais les NFs sont sévèrement altérés. Les NFs sont plus abondant, leur diamètre est augmenté et leur orientation hétérogène, comme c'est observé chez les patients NAG.Nos résultats montrent que l'absence de Gigaxonine induit un phénotype moteur et sensoriel modéré mais par contre reproduit la désorganisation massive des NFs observée chez les patients. Ce modèle va nous permettred'étudier le rôle de la Gigaxonine, une ligase E3, sur l'organisation des NFs et ainsi comprendre les processus pathologiques impliqués dans d'autres maladies neurodégénératives caractérisée par une accumulation des NFs et un dysfonctionnement du système ubiquitine-protéasome comme les maladies d'Azheimer, de Parkinson etd'huntington ou la sclérose latérale amyotrophique.Giant Axonal Neuropathy (GAN) is a rare and fatale neurodegenerative disorder characterized by a deterioration of the peripheral and central nervous system. The broad deterioration of the nervous system is accompanied with a general disorganization of the Intermediate Filaments which makes it different from other neurodegenerative disorders wherein only neurofilaments (NFs) are affected. The defective protein, Gigaxonin, is the substrate adaptator of an E3 ubiquitin ligase, in charge of the specific recognition of MAP1B, MAP1S and TBCB. In order to study the role of Gigaxonin on neuronal survival, the cytoskeleton disorganization and to have a relevant GAN animal model to evaluate efficacy of GAN treatments, I have characterized a GAN mouse model. I did a motor and sensory behavioural study and an histopathologic study. The GAN mice (129/SvJ) shown mild motordeficits starting at 60 weeks of age while sensory deficits were evidenced in C57BL/6 GAN mice. No apparent neurodegeneration was evidenced in GAN mice, but dysregulation of NFs was massive. NFs were more abundant, they shown the abnormal increased diameter and misorientation that are characteristics of the human pathology. Our results show that Gigaxonin depletion induces mild motor and sensory deficits but recapitulates the severe NFs dysregulation seen in patients. Our model will allow us to study the role of the Gigaxonin-E3 ligase in organizing NFs and understand the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of NFs and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases

Aurora Scrivo - One of the best experts on this subject based on the ideXlab platform.

  • Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production.
    Nature communications, 2019
    Co-Authors: Aurora Scrivo, Patrice Codogno, Pascale Bomont
    Abstract:

    Autophagy is an essential self-digestion machinery for cell survival and homoeostasis. Membrane elongation is fundamental, as it drives the formation of the double-membrane vesicles that engulf cytosolic material. LC3-lipidation, the signature of autophagosome formation, results from a complex ubiquitin-conjugating cascade orchestrated by the ATG16L1 protein, whose regulation is unknown. Here, we identify the Gigaxonin-E3 ligase as the first regulator of ATG16L1 turn-over and autophagosome production. Gigaxonin interacts with the WD40 domain of ATG16L1 to drive its ubiquitination and subsequent degradation. Gigaxonin depletion induces the formation of ATG16L1 aggregates and impairs LC3 lipidation, hence altering lysosomal fusion and degradation of the main autophagy receptor p62. Altogether, we demonstrate that the Gigaxonin-E3 ligase controls the production of autophagosomes by a reversible, ubiquitin-dependent process selective for ATG16L1. Our findings unveil the fundamental mechanisms of the control of autophagosome formation, and provide a molecular switch to fine-tune the activation of autophagy. Membrane elongation is fundamental to autophagy and is controlled by an ubiquitin-conjugating cascade orchestrated by ATG16L1. Here, the authors identify that the E3 ligase Gigaxonin regulates autophagosome formation by controlling ATG16L1 turnover.

  • Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production
    Nature Publishing Group, 2019
    Co-Authors: Aurora Scrivo, Patrice Codogno, Pascale Bomont
    Abstract:

    Membrane elongation is fundamental to autophagy and is controlled by an ubiquitin-conjugating cascade orchestrated by ATG16L1. Here, the authors identify that the E3 ligase Gigaxonin regulates autophagosome formation by controlling ATG16L1 turnover

Patrice Codogno - One of the best experts on this subject based on the ideXlab platform.

  • Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production.
    Nature communications, 2019
    Co-Authors: Aurora Scrivo, Patrice Codogno, Pascale Bomont
    Abstract:

    Autophagy is an essential self-digestion machinery for cell survival and homoeostasis. Membrane elongation is fundamental, as it drives the formation of the double-membrane vesicles that engulf cytosolic material. LC3-lipidation, the signature of autophagosome formation, results from a complex ubiquitin-conjugating cascade orchestrated by the ATG16L1 protein, whose regulation is unknown. Here, we identify the Gigaxonin-E3 ligase as the first regulator of ATG16L1 turn-over and autophagosome production. Gigaxonin interacts with the WD40 domain of ATG16L1 to drive its ubiquitination and subsequent degradation. Gigaxonin depletion induces the formation of ATG16L1 aggregates and impairs LC3 lipidation, hence altering lysosomal fusion and degradation of the main autophagy receptor p62. Altogether, we demonstrate that the Gigaxonin-E3 ligase controls the production of autophagosomes by a reversible, ubiquitin-dependent process selective for ATG16L1. Our findings unveil the fundamental mechanisms of the control of autophagosome formation, and provide a molecular switch to fine-tune the activation of autophagy. Membrane elongation is fundamental to autophagy and is controlled by an ubiquitin-conjugating cascade orchestrated by ATG16L1. Here, the authors identify that the E3 ligase Gigaxonin regulates autophagosome formation by controlling ATG16L1 turnover.

  • Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production
    Nature Publishing Group, 2019
    Co-Authors: Aurora Scrivo, Patrice Codogno, Pascale Bomont
    Abstract:

    Membrane elongation is fundamental to autophagy and is controlled by an ubiquitin-conjugating cascade orchestrated by ATG16L1. Here, the authors identify that the E3 ligase Gigaxonin regulates autophagosome formation by controlling ATG16L1 turnover