Dataset Information

Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model.

ABSTRACT: Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting ?3 in 100 000 individuals in Caucasian populations. It is caused by intronic GAA repeat expansions that hinder the expression of the FXN gene, resulting in defective levels of the mitochondrial protein frataxin. Sensory neurons in dorsal root ganglia (DRG) are particularly damaged by frataxin deficiency. There is no specific therapy for FRDA. Here, we show that frataxin levels can be upregulated by interferon gamma (IFN?) in a variety of cell types, including primary cells derived from FRDA patients. IFN? appears to act largely through a transcriptional mechanism on the FXN gene. Importantly, in vivo treatment with IFN? increases frataxin expression in DRG neurons, prevents their pathological changes and ameliorates the sensorimotor performance in FRDA mice. These results disclose new roles for IFN? in cellular metabolism and have direct implications for the treatment of FRDA.

SUBMITTER: Tomassini B

PROVIDER: S-EPMC3373236 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model.

Tomassini Barbara B Arcuri Gaetano G Fortuni Silvia S Sandi Chiranjeevi C Ezzatizadeh Vahid V Casali Carlo C Condò Ivano I Malisan Florence F Al-Mahdawi Sahar S Pook Mark M Testi Roberto R

Human molecular genetics 20120323 13

Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting ∼3 in 100 000 individuals in Caucasian populations. It is caused by intronic GAA repeat expansions that hinder the expression of the FXN gene, resulting in defective levels of the mitochondrial protein frataxin. Sensory neurons in dorsal root ganglia (DRG) are particularly damaged by frataxin deficiency. There is no specific therapy for FRDA. Here, we show that frataxin levels can be upregulated by interferon gamma (IFNγ) ...[more]

PMID: 22447512

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Project description:Background: Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAA/TTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. Methodology/Principal Findings: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)230 repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. Conclusions/Significance: Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease. Keywords: drug response

Dataset Information

Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model.

Publications

Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model.

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