Journal Article

Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination

Verum Foundation, Albaric, Olivier, Darios, Frédéric, Toulouse White Biotechnology (TWB), Guatteo, Raphaël, R., Esquerré, Diane, El Hachimi, Khalid Hamid, Beauvallet, Christian, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Saintilan, Romain, Stevanin, Giovanni, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière, Duchesne, Amandine, Vaiman, Anne, Fondation GIS-Maladies Rares, CHU Pitié-Salpêtrière, Venot, Eric, Frah, Magali, Bertaud, Maud, Boichard, Didier, Vilotte, Jean-Luc, Allice, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fleming, Anaïs, Legoueix, Sabrina, Fritz, Sebastien, ApisGene, Brice, Alexis, Génétique Animale et Biologie Intégrative (GABI), Génétique Physiologie et Systèmes d'Elevage (GenPhySE), Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), Desmazières, Anne, Floriot, Sandrine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-S

2018

Overview

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.

• Publisher: CCSD,Public Library of Science,Public Library of Science (PLoS)
• Subject: Actin / Animal biology / Ataxia / Bioinformatics / Biology and Life Sciences / Bovidae / Brain research / Cattle / Cattle diseases / Coding / Demyelination / Diseases / Funding / Gene mutation / Gene mutations / Gene polymorphism / Genetic aspects / Genomes / Health aspects / Hereditary spastic paraplegia / Isoforms / Life Sciences / Medicine and Health Sciences / Mimicry / Multiple sclerosis / Mutation / Myelination / Nervous system / Neural coding / Neurodegenerative diseases / NMR / Nuclear magnetic resonance / Oligodendrocytes / Paralysis / Plaques / Proteins / Research and Analysis Methods / Single-nucleotide polymorphism / Spastic paraplegia
• ISBN: 0004433891000