Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice.
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.
Fossale
Elisa
E
Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA.
Wheeler
Vanessa C
VC
Vrbanac
Vladimir
V
Lebel
Lori-Anne
LA
Teed
Allison
A
Mysore
Jayalakshmi S
JS
Gusella
James F
JF
MacDonald
Marcy E
ME
Persichetti
Francesca
F
D017668:Age of Onset; D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins; D019680:Trinucleotide Repeat Expansion
D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C405526:RRS1 protein, human