'Induced expression of expanded CGG RNA causes mitochondrial dysfunction in vivo.'
| Autor: | Rini de Crom, Chris Raske, Alex Maas, Robert F. Berman, Ingeborg Nieuwenhuizen-Bakker, Renate K. Hukema, Lies Anne Severijnen, Michelle Minneboo, Rob Willemsen, Johan M. Kros, Paul J. Hagerman, Ronald A.M. Buijsen |
|---|---|
| Přispěvatelé: | Clinical Genetics, Molecular Genetics, Cell biology, Pathology |
| Rok vydání: | 2014 |
| Předmět: |
Apoptosis
enhanced green fluorescent protein Mitochondrion Neurodegenerative Transgenic Repetitive Sequences Pathogenesis Mice eGFP caspase 3 Tremor 2.1 Biological and endogenous factors Aetiology Tet-On gpx Anti-Bacterial Agents Mitochondria Liver Doxycycline Neurological Fragile X-associated tremor/ataxia syndrome ataxia syndrome medicine.symptom rtTA Genetically modified mouse dox congenital hereditary and neonatal diseases and abnormalities Ataxia Transgene Intellectual and Developmental Disabilities (IDD) inducible mouse model Biology Promoter Regions cytochrome C Rare Diseases Genetic In vivo Report medicine Genetics Animals Molecular Biology Repetitive Sequences Nucleic Acid Nucleic Acid Animal gpx-1 Neurosciences RNA Cell Biology Molecular biology reverse tetracycline transactivator Brain Disorders Fatty Liver Orphan Drug Fragile X-associated tremor CGG repeat Tet Responsive Element gluthation peroxidase Fragile X Syndrome Disease Models FXTAS TRE Biochemistry and Cell Biology Reactive Oxygen Species RNA gain-of-function Developmental Biology |
| Zdroj: | Cell Cycle, 13, 2600-2608. Landes Bioscience Cell cycle (Georgetown, Tex.), vol 13, iss 16 |
| ISSN: | 1538-4101 |
| Popis: | Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation forms of the FMR1 gene, resulting in a progressive development of tremor, ataxia and neuropsychological problems. The disease is caused by an expanded CGG repeat in the FMR1 gene, leading to an RNA gain-of-function toxicity mechanism. In order to study the pathogenesis of FXTAS, new inducible transgenic mouse models have been developed that expresses either 11CGGs or 90CGGs at the RNA level under control of a Tet-On promoter. When bred to an hnRNP-rtTA driver line, doxycycline (dox) induced expression of the transgene could be found in almost all tissues. Dox exposure resulted in loss of weight and death within 5 d for the 90CGG RNA expressing mice. Immunohistochemical examination of tissues of these mice revealed steatosis and apoptosis in the liver. Decreased expression of GPX1 and increased expression of cytochrome C is found. These effects were not seen in mice expressing a normal sized 11CGG repeat. In conclusion, we were able to show in vivo that expression of an expanded CGG-repeat rather than overexpression of a normal CGG-repeat causes pathology. In addition, we have shown that expanded CGG RNA expression can cause mitochondrial dysfunction by regulating expression levels of several markers. Although FTXAS patients do not display liver abnormalities, our findings contribute to understanding of the molecular mechanisms underlying toxicity of CGG repeat RNA expression in an animal model. In addition, the dox inducible mouse lines offer new opportunities to study therapeutic interventions for FXTAS. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|