Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination
| Autor: | Raphaël Guatteo, Diane Esquerre, Sabrina Legoueix-Rodriguez, Maud Bertaud, Anaïs Fleming, Julien Branchu, Christian Beauvallet, Romain Saintilan, Alexis Brice, Amandine Duchesne, Anne Vaiman, Frédéric Darios, Anne Desmazières, Giovanni Stevanin, Sandrine Floriot, Magali Frah, Olivier Albaric, Eric Venot, Khalid Hamid El Hachimi, Sébastien Fritz, Jean-Luc Vilotte, Didier Boichard |
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| Přispěvatelé: | Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Université Paris Saclay (COmUE), Sorbonne Universités (COMUE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Toulouse White Biotechnology (TWB), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées, Allice, Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), Institut National de la Recherche Agronomique (INRA), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), INRA Animal Genetics Department, ApisGene, French National Research Agency [ANR14_CE 19-0011, ANR-13-ISV1-00002], 'Investissements d’avenir' programme [ANR-10-IAIHU-06, ANR11-INBS-0011], Verum Foundation, Fondation GIS-Maladies Rares, Fondation Roger de Spoelberch, Seventh Framework Programme - FP7 (Omics), ERare programme (Neurolipid), Duchesne, Amandine, El Hachimi, Khalid Hamid, Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ProdInra, Migration, Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-École nationale supérieure agronomique de Toulouse (ENSAT), Université de Toulouse (UT)-Université de Toulouse (UT), École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Central Nervous System
Male 0301 basic medicine Cancer Research bovin [SDV.BA] Life Sciences [q-bio]/Animal biology Cell Membranes Kinesins gène kif1c Immunostaining medicine.disease_cause Nervous System Myelin 0302 clinical medicine Medicine and Health Sciences Missense mutation Myelin Sheath Genetics (clinical) Spinocerebellar Degenerations Mammals Staining Animal biology 2. Zero hunger Genetics Mutation Movement Disorders biology [SDV.BA]Life Sciences [q-bio]/Animal biology Homozygote Eukaryota Neurodegenerative Diseases Ruminants anomalie génétique ataxie progressive démyélinisation medicine.anatomical_structure Neurology Veterinary Diseases Spinal Cord Muscle Spasticity Vertebrates Female Anatomy Cellular Structures and Organelles medicine.symptom Research Article Heterozygote Ataxia lcsh:QH426-470 biology.animal_breed Mutation Missense Cattle Diseases Single-nucleotide polymorphism Research and Analysis Methods Polymorphism Single Nucleotide 03 medical and health sciences Bovines Intellectual Disability Biologie animale medicine Animals Spinocerebellar Ataxias Amino Acid Sequence Allele Molecular Biology Ecology Evolution Behavior and Systematics Whole Genome Sequencing Spastic Paraplegia Hereditary Genetic heterogeneity Organisms Biology and Life Sciences Membrane Proteins Cell Biology Neuroanatomy Disease Models Animal Optic Atrophy lcsh:Genetics 030104 developmental biology Specimen Preparation and Treatment Amniotes Cattle Veterinary Science 030217 neurology & neurosurgery Charolais cattle Neuroscience |
| Zdroj: | PLoS Genetics PLoS Genetics, Public Library of Science, 2018, 14 (8), pp.1-25. ⟨10.1371/journal.pgen.1007550⟩ Plos Genetics 8 (14), 1-25. (2018) PLoS Genetics, 2018, 14 (8), pp.1-25. ⟨10.1371/journal.pgen.1007550⟩ PLoS Genetics, Vol 14, Iss 8, p e1007550 (2018) |
| ISSN: | 1553-7390 1553-7404 |
| Popis: | Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous human neurodegenerative diseases. Amongst the identified genetic causes, mutations in genes encoding motor proteins such as kinesins have been involved in various HSP clinical isoforms. Mutations in KIF1C are responsible for autosomal recessive spastic paraplegia type 58 (SPG58) and spastic ataxia 2 (SPAX2). Bovines also develop neurodegenerative diseases, some of them having a genetic aetiology. Bovine progressive ataxia was first described in the Charolais breed in the early 1970s in England and further cases in this breed were subsequently reported worldwide. We can now report that progressive ataxia of Charolais cattle results from a homozygous single nucleotide polymorphism in the coding region of the KIF1C gene. In this study, we show that the mutation at the heterozygous state is associated with a better score for muscular development, explaining its balancing selection for several decades, and the resulting high frequency (13%) of the allele in the French Charolais breed. We demonstrate that the KIF1C bovine mutation leads to a functional knock-out, therefore mimicking mutations in humans affected by SPG58/SPAX2. The functional consequences of KIF1C loss of function in cattle were also histologically reevaluated. We showed by an immunochemistry approach that demyelinating plaques were due to altered oligodendrocyte membrane protrusion, and we highlight an abnormal accumulation of actin in the core of demyelinating plaques, which is normally concentrated at the leading edge of oligodendrocytes during axon wrapping. We also observed that the lesions were associated with abnormal extension of paranodal sections. Moreover, this model highlights the role of KIF1C protein in preserving the structural integrity and function of myelin, since the clinical signs and lesions arise in young-adult Charolais cattle. Finally, this model provides useful information for SPG58/SPAX2 disease and other demyelinating lesions. Author summary Hereditary spastic paraplegias (HSPs) are human neurodegenerative diseases mainly associated with lower extremity weakness and spasticity. Motor-sensory axons degeneration, implying heterogeneous cellular and molecular mechanisms and various genetic causes, is the neuropathological hallmark of this disease. Recently, mutations in KIF1C were associated with human spastic paraplegia type 58 (SPG58) and spastic ataxia 2 (SPAX2), where the radiological brain examination showed demyelination features. We report herein that progressive ataxia of Charolais cattle, a neurodegenerative disease with autosomal recessive inheritance, is caused by a substitution in the KIF1C gene, which leads to a functional knock-out. Interestingly this mutation is associated, in a heterozygous state, with a better muscular development, and thus a zootechnic advantage. Identification of the mutation will therefore be helpful to eradicate this disease. Further study of the lesions in ataxic bovine central nervous system highlighted a peculiar link to oligodendrocytes which were hypertrophied and harbored many membrane protrusions. The demyelinating plaques were enriched by these membranes and actin accumulation indicating close relationship between KIF1C, actin transport and axonal wrapping by oligodendrocyte tongues. Since kif1c knock-out mouse do not display any neurological symptoms, progressive ataxia of Charolais cattle thus provides a useful model for studying SPG58/SPAX2 and other demyelinating diseases. |
| Databáze: | OpenAIRE |
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