Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination
Year: 2018
Type: article
Abstract: 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.
Source: PLoS Genetics
Authors: Amandine Duchesne, Anne Vaiman, Magali Frah, Sandrine Floriot, Sabrina Legoueix-Rodriguez, Anne Desmazières, Sébastien Fritz, Christian Beauvallet, Olivier Albaric, Eric Venot, Maud Bertaud, Romain Saintilan, Raphaël Guatteo, Diane Esquerré, Julien Branchu, Anaïs Fleming, Alexis Brice, Frédéric Darios, Jean-Luc Vilotte, Giovanni Stevanin, Didier Boichard, Khalid Hamid El Hachimi
Institutions: AgroParisTech, Université Paris-Saclay, Génétique Animale et Biologie Intégrative, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Institut des Sciences Moléculaires, Institut du Cerveau, Institut National des Sciences Appliquées de Toulouse, Institut National de la Recherche Agronomique, Université de Toulouse, Toulouse White Biotechnology, Université Nantes Angers Le Mans, Oniris, Biologie, Epidémiologie et Analyse de Risque en Santé Animale, École Nationale Vétérinaire de Toulouse, Institut National Polytechnique de Toulouse, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Génétique Physiologie et Systèmes d'Elevage, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, École Pratique des Hautes Études, Université Paris Sciences et Lettres
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Awards: G1154253492, G1258743643, Identification and functional study of cattle deleterious mutations, Identification of new causative genes in spinocerebellar degenerations by combination of whole genome scan, next-generation sequencing and biological validation in vitro and in vivo, G6762165520, Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences
OpenAlex ID: W2887332553