| First Author | Fossale E | Year | 2002 |
| Journal | Hum Mol Genet | Volume | 11 |
| Issue | 19 | Pages | 2233-41 |
| PubMed ID | 12217951 | Mgi Jnum | J:79126 |
| Mgi Id | MGI:2387255 | Doi | 10.1093/hmg/11.19.2233 |
| Citation | Fossale E, et al. (2002) Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice. Hum Mol Genet 11(19):2233-41 |
| abstractText | The hallmark striatal neurodegeneration of Huntington's disease (HD) is first triggered by a dominant property of the expanded glutamine tract in mutant huntingtin that increases in severity with glutamine size. Indeed 111-glutamine murine huntingtin leads to a dominant cascade of phenotypes in Hdh(Q111) mice, although these abnormalities are not manifest in Hdh(Q50) mice, with 50-glutamine mutant protein. Therefore, to identify phenotypes that might reflect events closer to the fundamental trigger mechanism, and that can be measured as a consequence of adult-onset HD mutant huntingtin, we have screened for altered expression of genes conserved in evolution, which are likely to encode essential proteins. Probes generated from Hdh(Q111) homozygote and wild-type striatal RNAs were hybridized to human gene segments on filter arrays, disclosing a mutant-specific increase in hybridization to Rrs1, encoding a ribosomal protein. Subsequent, quantitative RT-PCR assays demonstrated increased Rrs1 mRNA from 3 weeks of age in homozygous and heterozygous Hdh(Q111) striatum and increased Rrs1 mRNA expression with a single copy's worth of 50-glutamine mutant huntingtin in Hdh(Q50) striatum. Moreover, quantitative RT-PCR assays for the human homologue demonstrated elevated Rrs1 mRNA in HD compared with control postmortem brain. These findings, therefore, support a chronic impact of mutant huntingtin on an essential ribosomal regulatory gene to be investigated for its role very early in HD pathogenesis. |
