Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype
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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-08-01
|
| Series: | Genes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4425/14/8/1654 |
| _version_ | 1797584619110924288 |
|---|---|
| author | Camille Bouchard Catherine Gérard Solange Gni-fiene Yanyabé Nathalie Majeau Malek Aloui Gabrielle Buisson Pouiré Yameogo Vanessa Couture Jacques P. Tremblay |
| author_facet | Camille Bouchard Catherine Gérard Solange Gni-fiene Yanyabé Nathalie Majeau Malek Aloui Gabrielle Buisson Pouiré Yameogo Vanessa Couture Jacques P. Tremblay |
| author_sort | Camille Bouchard |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T23:54:13Z |
| format | Article |
| id | doaj.art-494b27f57cca4621b035931f4dd65348 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T23:54:13Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-494b27f57cca4621b035931f4dd653482023-11-19T01:16:37ZengMDPI AGGenes2073-44252023-08-01148165410.3390/genes14081654Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral PhenotypeCamille Bouchard0Catherine Gérard1Solange Gni-fiene Yanyabé2Nathalie Majeau3Malek Aloui4Gabrielle Buisson5Pouiré Yameogo6Vanessa Couture7Jacques P. Tremblay8Centre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaCentre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaCentre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaCentre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaCentre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaCentre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaCentre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaCentre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaCentre de Recherche du CHU, Québec-Université Laval, Québec, QC G1V 4G2, CanadaFriedreich 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.https://www.mdpi.com/2073-4425/14/8/1654Friedreich ataxiamouse modelphenotypefrataxinshRNA |
| spellingShingle | Camille Bouchard Catherine Gérard Solange Gni-fiene Yanyabé Nathalie Majeau Malek Aloui Gabrielle Buisson Pouiré Yameogo Vanessa Couture Jacques P. Tremblay Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype Genes Friedreich ataxia mouse model phenotype frataxin shRNA |
| title | Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype |
| title_full | Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype |
| title_fullStr | Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype |
| title_full_unstemmed | Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype |
| title_short | Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype |
| title_sort | finding an appropriate mouse model to study the impact of a treatment for friedreich ataxia on the behavioral phenotype |
| topic | Friedreich ataxia mouse model phenotype frataxin shRNA |
| url | https://www.mdpi.com/2073-4425/14/8/1654 |
| work_keys_str_mv | AT camillebouchard findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype AT catherinegerard findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype AT solangegnifieneyanyabe findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype AT nathaliemajeau findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype AT malekaloui findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype AT gabriellebuisson findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype AT pouireyameogo findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype AT vanessacouture findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype AT jacquesptremblay findinganappropriatemousemodeltostudytheimpactofatreatmentforfriedreichataxiaonthebehavioralphenotype |