RESUMEN
Polyglutamine (PolyQ) diseases have common features that include progressive selective neurodegeneration and the formation of protein aggregates. There is growing evidence to suggest that critical nuclear events lead to transcriptional alterations in PolyQ diseases such as spinocerebellar ataxia type 7 (SCA7) and Huntington's disease (HD), conditions which share a cerebellar degenerative phenotype. Taking advantage of laser capture microdissection technique, we compared the Purkinje cell (PC) gene expression profiles of two transgenic polyQ mouse models (HD: R6/2; SCA7: P7E) by microarray analysis that was validated by real time quantitative PCR. A large number of transcriptional alterations were detected in the R6/2 transgenic model of HD. Similar decreases in the same mRNAs, such as phospholipase C, ß 3, purkinje cell protein 2 (Pcp2) and aldolase C, were found in both models. A decrease in aldolase C and phospholipase C, ß 3, may lead to an increase in the vulnerability of PCs to excitotoxic events. Furthermore, downregulation of mRNAs mediated by the Pcp2-promoter is common in both models. Thus, our data reveal shared molecular abnormalities in different polyQ disorders.
Asunto(s)
Enfermedad de Huntington/genética , Proteínas del Tejido Nervioso/genética , Péptidos/genética , Células de Purkinje/fisiología , Ataxias Espinocerebelosas/genética , Animales , Ataxina-7 , Modelos Animales de Enfermedad , Femenino , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Proteína Huntingtina , Enfermedad de Huntington/patología , Ratones , Ratones Transgénicos , Neuropéptidos/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas/genética , Células de Purkinje/patología , Ataxias Espinocerebelosas/patología , Transcriptoma , Transgenes/genéticaRESUMEN
Ataxia is a clinical feature of most polyglutamine disorders. Cerebellar neurodegeneration of Purkinje cells (PCs) in Huntington's Disease (HD) brain was described in the 1980s. PC death in the R6/2 transgenic model for HD was published by Turmaine et al. So far, PCs have not been examined on a single cell level. In order to begin to understand PC dysfunction and degeneration in HD we performed a gene expression study on laser-dissected PC based on a DNA microarray screening and quantitative real time PCR (Q-PCR). We demonstrate downregulation of the retinoid acid receptor-related orphan receptor (ROR) mRNA and ROR-mediated mRNAs, also seen by immunofluorescent staining. As ROR and ROR-dependent transcriptional dysregulation is not only found in the R6/2 model for HD but also in a model for spinocerebellar ataxia type 1 (SCA1) (Serra et al.) the data suggest common pathogenic mechanisms for both polyglutamine diseases.