Abstract
BackgroundFriedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions.Methodology/Principal FindingsTo determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription.Conclusions/SignificanceBoth MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription.
Highlights
Friedreich ataxia (FRDA) is a fatal, autosomal recessive neurodegenerative disorder caused by homozygous GAA repeat expansion within intron 1 of the FXN gene [1]
By analyzing intergenerational transmissions of YG8 and YG22 mouse models, we have demonstrated that deficit of any of the Msh2, Msh3, Msh6 or Pms2 parental mismatch repair (MMR) proteins increases GAA repeat mutability in the offspring
Mlh1 activity promotes somatic GAA repeat expansions We have previously demonstrated that loss of Pms2 leads to increased GAA repeat expansions in FRDA-relevant tissues, namely brain, cerebellum and dorsal root ganglia (DRG) [27]
Summary
Friedreich ataxia (FRDA) is a fatal, autosomal recessive neurodegenerative disorder caused by homozygous GAA repeat expansion within intron 1 of the FXN gene [1]. This mutation induces heterochromatin formation [2], likely due to abnormal non-B DNA or DNANRNA hybrid triplex structures [3,4], leading to FXN gene silencing and reduced expression of the essential mitochondrial protein, frataxin [5]. Friedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLa complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.