Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice

Elisa Fossale, Vanessa C. Wheeler, Vladimir Vrbanac, Lori Anne Lebel, Allison Teed, Jayalakshmi S. Mysore, James F. Gusella, Marcy E. MacDonald, Francesca Persichetti

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

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.

Lingua originaleInglese
pagine (da-a)2233-2241
Numero di pagine9
RivistaHuman Molecular Genetics
Volume11
Numero di pubblicazione19
DOI
Stato di pubblicazionePubblicato - 15 set 2002
Pubblicato esternamente

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