Induced expression of expanded CGG RNA causes mitochondrial dysfunction in vivo.
Cell Cycle
; 13(16): 2600-8, 2014.
Article
em En
| MEDLINE
| ID: mdl-25486200
ABSTRACT
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.
Palavras-chave
CGG repeat; FXTAS; FXTAS, Fragile X-associated tremor/ataxia syndrome; RNA gain-of-function; TRE, Tet Responsive Element; Tet-On; apoptosis; caspase 3; cytochrome C; dox, doxycycline; eGFP, enhanced green fluorescent protein; gpx, gluthation peroxidase; gpx-1; inducible mouse model; mitochondria; rtTA, reverse tetracycline transactivator
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Ataxia
/
Tremor
/
RNA
/
Sequências Repetitivas de Ácido Nucleico
/
Síndrome do Cromossomo X Frágil
/
Mitocôndrias
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cell Cycle
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Holanda