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A novel GAA-repeat-expansion-based mouse model of Friedreich's ataxia.

Abstract
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a GAA repeat expansion mutation within intron 1 of the FXN gene, resulting in reduced levels of frataxin protein. We have previously reported the generation of human FXN yeast artificial chromosome (YAC) transgenic FRDA mouse models containing 90-190 GAA repeats, but the presence of multiple GAA repeats within these mice is considered suboptimal. We now describe the cellular, molecular and behavioural characterisation of a newly developed YAC transgenic FRDA mouse model, designated YG8sR, which we have shown by DNA sequencing to contain a single pure GAA repeat expansion. The founder YG8sR mouse contained 120 GAA repeats but, due to intergenerational expansion, we have now established a colony of YG8sR mice that contain ~200 GAA repeats. We show that YG8sR mice have a single copy of the FXN transgene, which is integrated at a single site as confirmed by fluorescence in situ hybridisation (FISH) analysis of metaphase and interphase chromosomes. We have identified significant behavioural deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8sR FRDA mice compared with control Y47R and wild-type (WT) mice. We have also detected increased somatic GAA repeat instability in the brain and cerebellum of YG8sR mice, together with significantly reduced expression of FXN, FAST-1 and frataxin, and reduced aconitase activity, compared with Y47R mice. Furthermore, we have confirmed the presence of pathological vacuoles within neurons of the dorsal root ganglia (DRG) of YG8sR mice. These novel GAA-repeat-expansion-based YAC transgenic FRDA mice, which exhibit progressive FRDA-like pathology, represent an excellent model for the investigation of FRDA disease mechanisms and therapy.
AuthorsSara Anjomani Virmouni, Vahid Ezzatizadeh, Chiranjeevi Sandi, Madhavi Sandi, Sahar Al-Mahdawi, Yogesh Chutake, Mark A Pook
JournalDisease models & mechanisms (Dis Model Mech) Vol. 8 Issue 3 Pg. 225-35 (Mar 2015) ISSN: 1754-8411 [Electronic] England
PMID25681319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015. Published by The Company of Biologists Ltd.
Chemical References
  • Forkhead Transcription Factors
  • Iron-Binding Proteins
  • RNA, Messenger
  • frataxin
  • Aconitate Hydratase
Topics
  • Aconitate Hydratase (metabolism)
  • Animals
  • Behavior, Animal
  • Body Weight
  • Disease Models, Animal
  • Forkhead Transcription Factors (metabolism)
  • Friedreich Ataxia (complications, genetics, pathology)
  • Ganglia, Spinal (metabolism, pathology)
  • Gene Dosage
  • Glucose Intolerance (complications, pathology)
  • Hand Strength
  • Humans
  • Iron-Binding Proteins (genetics, metabolism)
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • RNA, Messenger (genetics, metabolism)
  • Rotarod Performance Test
  • Transgenes
  • Trinucleotide Repeat Expansion (genetics)

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