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Progressive ataxia is a neurodegenerative disorder described in Charolais cattle since the 1970s. It affects the welfare of affected animals and is very costly for breeding because of its late expression. Indeed, around 18 months, young cattle show a progressive paralysis of the hind limbs leading to death. Work conducted by INRA confirmed the recessive determinism of this condition and made it possible to identify the mutation responsible in the KIF1C gene.
Since this gene is associated with cases of hereditary spastic paraplegia in humans, a collaboration with a team from the ICM (Institut du Cerveau et de la Moelle épinière) made it possible to exploit this bovine model to advance our understanding of the physiopathology of these anomalies. This work was published in Plos Genetics magazine on August 1, 2018.

Since 1972, a new anomaly has been identified in Charolais cattle in various countries: progressive ataxia. Affected cattle, of both sexes, develop between 12 and 18 months of age an incoordination and stiffness of the hind limbs. These symptoms worsen in the months that follow, until paralysis of the limbs and death. The first histopathological studies show characteristic lesions exclusively in the central nervous system, mainly affecting the white matter. Genetic etiology has long been suspected but not confirmed.
In France, the establishment of the Observatoire National des Anomalies Bovines (ONAB, www.onab.fr) in 2002 and the active assistance of a few attentive veterinarians have made it possible to observe this emergence of progressive ataxia. A total of 71 cases have been described over the past 15 years, leading INRA to launch a program to characterize this anomaly.

The genotyping of about forty cases on SNP chips made it possible to validate the exclusively genetic determinism of the anomaly, with an autosomal recessive mode of transmission. Genome sequencing of 2 diseased animals identified the causal mutation in the KIF1C (Kinesin Family member 1C) gene, a non-synonymous substitution in the coding portion associated with an extinction of KIF1C protein expression in nerve tissue. This mutation seems ancient: despite a good knowledge of pedigrees over 12 generations, no ancestor could be identified as solely responsible for its spread. Associated with the heterozygous state to a better skeletal and muscular conformation, it has not been eliminated by natural selection. A molecular test is now available and constitutes a tool of choice to manage this anomaly, which is both costly for breeding and detrimental to animal welfare. On the one hand, the frequency of the mutated allele should decrease in the population due to the selection effort, on the other hand the number of cases should be very limited by avoiding risky matings.

But beyond its impact on animal husbandry, cattle have constituted a model for studying similar human pathologies. Indeed, biological material has been collected from cases, which is impossible in humans. Moreover, in mice, the invalidation of the KIF1C gene does not produce any phenotype. In humans, hereditary spastic paraplegia (HSP) form a clinically and genetically heterogeneous pattern of neurodegenerative abnormalities. The call sign is a weakness and spasticity of the lower limbs, clinical consequence of the degeneration of the cortico-spinal axons. To date, over 70 different genetic types have been described, including genes encoding kinesins. In humans, mutations in the KIF1C gene are associated with hereditary spastic paraplegia type 58 (SPG58/SPAX2). Brain imaging shows foci of demyelination. The cellular nature of the lesion remains unknown. The collaboration initiated between the two teams from INRA and ICM made it possible to show that ataxic cattle could be considered as the first natural animal model of GSP58. The bovine model provides an opportunity to better understand the physiopathology of the anomaly, including the cellular and molecular nature of the demyelinating plaque.

Myelin lesions rarely larger than 100 micrometers in diameter affect several tracts (brain, cerebellum and spinal cord). The starting point of the lesion is the oligodendrocyte. Alteration of KIF1C expression impacts actin transport from the cytoplasm to the oligodendrocyte winding segments, emphasizing the role of this kinesin in maintaining myelin structural and functional integrity.

Charolais progressive ataxia is a natural animal model for the study of hereditary spastic paraplegia type 58 (SPG58/SPAX2). More generally, it also offers a demyelinating disease study model.

Reference

Duchesne A, Vaiman A, Frah M, Floriot S, Legoueix-Rodriguez S, Desmazières A, Fritz S, Beauvallet C, Albaric O, Venot E, Bertaud M, Saintilan R, Guatteo R, Esquerré D, Branchu J, Fleming A, Brice A, Darios F, Vilotte JL, Stevanin G, Boichard D, El Hachimi KH. 2018. Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination. Plos Genetics, 14(8): e1007550. 

Contact

Unité Génétique Animale et Biologie Intégrative (UMR1313 GABI), Jouy-en-Josas

• Amandine Duchesne