TY - JOUR
T1 - Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice
AU - Fossale, Elisa
AU - Wheeler, Vanessa C.
AU - Vrbanac, Vladimir
AU - Lebel, Lori Anne
AU - Teed, Allison
AU - Mysore, Jayalakshmi S.
AU - Gusella, James F.
AU - MacDonald, Marcy E.
AU - Persichetti, Francesca
PY - 2002/9/15
Y1 - 2002/9/15
N2 - 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 HdhQ111 mice, although these abnormalities are not manifest in HdhQ50 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 HdhQ111 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 HdhQ111 striatum and increased Rrs1 mRNA expression with a single copy's worth of 50-glutamine mutant huntingtin in HdhQ50 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.
AB - 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 HdhQ111 mice, although these abnormalities are not manifest in HdhQ50 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 HdhQ111 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 HdhQ111 striatum and increased Rrs1 mRNA expression with a single copy's worth of 50-glutamine mutant huntingtin in HdhQ50 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.
UR - http://www.scopus.com/inward/record.url?scp=0037106316&partnerID=8YFLogxK
U2 - 10.1093/hmg/11.19.2233
DO - 10.1093/hmg/11.19.2233
M3 - Article
SN - 0964-6906
VL - 11
SP - 2233
EP - 2241
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 19
ER -