Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype

Abstract

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a GAA repeat in the intron 1 of the frataxin gene (FXN) leading to a lower expression of the frataxin protein. The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. We aimed to find an optimized mouse model with a phenotype comparable to the human patients to study the impact of therapy on the phenotype. We compared two mouse models: the YG8sR injected with an AAV. PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats. Both mouse models were compared to Y47R mice containing nine GAA repeats that were considered healthy mice. Behavior tests (parallel rod floor apparatus, hanging test, inverted T beam, and notched beam test) were carried out from 2 to 11 months and significant differences were noticed for both YG8sR mice injected with an anti-FXN shRNA and the YG8-800 mice compared to healthy mice. In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing an shRNA targeting frataxin does increase their phenotype. The YG8-800 mice have a phenotype comparable to the human ataxic phenotype.

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich’s ataxia

“…The novel YG8-800 mouse is probably the most promising animal model for the study of the FRDA-disease mechanisms up to date. Despite some controversy regarding heart disease in this model, previous studies have shown that these mice have, among others, a behavioral phenotype of varying severity but comparable to movement coordination problems observed in FRDA patients, reduced aconitase activity, and epigenetic changes [21][22][23]39]. Therefore, in this work, we aimed at characterizing the disease progression regarding the neurodegenerative/inflammatory processes in the cerebellar cortex of these YG8-800 mice, comparing the results with the corresponding control strain.…”

“…The YG8-800 mouse model is based on previous versions of the same model but with a higher number of GAA repeats inserted in the FXN gene, which results in even lower FXN levels [20]. Recent reports indicate that affected mice have poor motor coordination reflecting muscular atrophy and signs of cardiac hypertrophy as early as 6 months of age, reduced aconitase activity, and epigenetic changes [21][22][23]. In this work, we characterized the phenotype of YG8-800 mice and the control strain Y47R (that harbors a normal human FXN gene) at the behavioral, histopathological, and biochemical level across different ages.…”

Study on Genotypes and Phenotypes of Neurodegenerative Diseases

“…The availability of affordable disease models is fundamental to the ongoing search for novel therapeutic approaches. Camille Bouchard and colleagues reported the discovery of a suitable mouse model for Friedreich’s Ataxia (FRDA), which is a progressive neurodegenerative disease caused by a triplet repeat in the frataxin gene ( FXN ) that leads to a reduced expression of the frataxin protein [ 6 ]. The previously used mouse model (YG8sR mice) showed a milder phenotype compared to human patients, limiting the ability to study the impact of therapy on the phenotype.…”