A new FRDA mouse model [Fxnnull:YG8s(GAA) &gt; 800] with more than 800 GAA repeats

Kalef-Ezra, Ester; Edzeamey, Fred Jonathan; Valle, Adamo; Khonsari, H; Kleine, Paula; Oggianu, Carlo; Al-Mahdawi, Sahar; Pook, Mark A.; Virmouni, Sara Anjomani

doi:10.3389/fnins.2023.930422

Cited by 9 publications

(10 citation statements)

References 65 publications

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“…Notably, YG8-800 mice showed a phenotype that resembles an ataxic behavior characterized by uncoordinated movements and gait instability. By analyzing locomotor function with the rotarod test, we have shown that YG8-800 mice exhibit deficits in motor coordination that start at 6 months of age, a time point slightly later compared to the findings reported by Kalef-Ezra et al [23]. Discrepancies in results between studies could be attributed to variations in the experimental protocols with more restrictive and prolonged ages studied, as well as larger sample sizes used in this work.…”

Section: Discussionmentioning

confidence: 44%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Vicente-Acosta,

Herranz-Martín,

Pazos

et al. 2024

Preprint

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Friedreich's ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the FXN gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, some of the main symptoms observed in affected individuals. Similar to other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in Friedreich's ataxia. In this work, we have followed and characterized the progression of changes in the cerebellar cortex of the latest Friedreich's ataxia humanized mouse model, the YG8-800 (Fxnnull:YG8s(GAA)>800), which carries a human FXN transgene containing more than 800 GAA repeats. Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between Y47R control and YG8-800 mice at different time points. Our findings revealed that the YG8-800 mice display an ataxic phenotype, characterized by poor motor coordination, lower body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration along with an increased expression of key pro-inflammatory cytokines and downregulation of neurotrophic factors. Together, our results show how the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in the human condition. Accordingly, this humanized model could represent a valuable tool to study Friedreich's ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.

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Section: Discussionmentioning

confidence: 44%

Section: Introductionmentioning

confidence: 99%

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

Vicente-Acosta,

Herranz-Martín,

Pazos

et al. 2024

Preprint

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“…Though quite rare, large intergenerational repeat expansions in mouse RED models have been noted, including the C9orf72 G 4 C 2 repeats ( 19 , 70 , 87 , 88 ). These are sporadic events, and it is not clear what factors cause large intergenerational repeat expansions.…”

Section: Resultsmentioning

confidence: 99%

“…The major repeat expansions induced by DNA DSB/SSB and their application for disease modelling (Figures 3 and 8 ) represents a new paradigm to create RED models in a genetically-tractable mammalian system. The magnitude of repeat expansion seen in humans is difficult to reproduce in the mouse models with some exceptions ( 19 , 70 , 87 , 88 ). Hence, it has been difficult to generate RED mouse models containing large STRs.…”

Section: Discussionmentioning

confidence: 99%

Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model

Kojak,

Kuno,

Fittipaldi

et al. 2024

Nucleic Acids Research

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Expansion of a G4C2 repeat in the C9orf72 gene is associated with familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). To investigate the underlying mechanisms of repeat instability, which occurs both somatically and intergenerationally, we created a novel mouse model of familial ALS/FTD that harbors 96 copies of G4C2 repeats at a humanized C9orf72 locus. In mouse embryonic stem cells, we observed two modes of repeat expansion. First, we noted minor increases in repeat length per expansion event, which was dependent on a mismatch repair pathway protein Msh2. Second, we found major increases in repeat length per event when a DNA double- or single-strand break (DSB/SSB) was artificially introduced proximal to the repeats, and which was dependent on the homology-directed repair (HDR) pathway. In mice, the first mode primarily drove somatic repeat expansion. Major changes in repeat length, including expansion, were observed when SSB was introduced in one-cell embryos, or intergenerationally without DSB/SSB introduction if G4C2 repeats exceeded 400 copies, although spontaneous HDR-mediated expansion has yet to be identified. These findings provide a novel strategy to model repeat expansion in a non-human genome and offer insights into the mechanism behind C9orf72 G4C2 repeat instability.

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“…In September 2022, our team published the characterization of this mouse model including the cardiac hypertrophy which is also part of the human phenotype [ 45 ]. In January 2023, Kalef-Ezra et al confirmed the impaired coordination and reduced frataxin levels of the mouse model [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

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

Bouchard,

Gérard,

Yanyabé

et al. 2023

Genes

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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.

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A new FRDA mouse model [Fxnnull:YG8s(GAA) > 800] with more than 800 GAA repeats

Cited by 9 publications

References 65 publications

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

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

Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model

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

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