Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage

被引:263
作者
Kuhn, Alexandre
Goldstein, Darlene R.
Hodges, Angela
Strand, Andrew D.
Sengstag, Thierry
Kooperberg, Charles
Becanovic, Kristina
Pouladi, Mahmoud A.
Sathasivam, Kirupa
Cha, Jang-Ho J.
Hannan, Anthony J.
Hayden, Michael R.
Leavitt, Blair R.
Dunnett, Stephen B.
Ferrante, Robert J.
Albin, Roger
Shelbourne, Peggy
Delorenzi, Mauro
Augood, Sarah J.
Faull, Richard L. M.
Olson, James M.
Bates, Gillian P.
Jones, Lesley
Luthi-Carter, Ruth
机构
[1] Ecole Polytech Fed Lausanne, CH-1015 Lausanne, Switzerland
[2] Swiss Inst Expt Canc Res, Natl Ctr Competence Res NCCR Mol Oncol, CH-1066 Epalinges, Switzerland
[3] SIB, CH-1066 Epalinges, Switzerland
[4] Cardiff Univ, Dept Psychol Med, Cardiff CF14 4XN, Wales
[5] Cardiff Univ, Dept Med Genet & Med, Cardiff CF14 4XN, Wales
[6] Cardiff Univ, Sch Biosci, Cardiff CF14 4XN, Wales
[7] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA
[8] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 4H4, Canada
[9] Child & Family Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada
[10] Kings Coll London, Sch Med, Dept Med & Mol Genet, London SE1 9RT, England
[11] Massachusetts Gen Hosp East, MassGen Inst Neurodegenerat Dis MIND, Charlestown, MA 02129 USA
[12] Univ Oxford, Physiol Lab, Oxford OX1 3PT, England
[13] Univ Melbourne, Natl Neurosci Facil, Howard Florey Inst, Melbourne, Vic 3010, Australia
[14] Boston Univ, Sch Med, Dept Neurol, Bedford, MA USA
[15] Boston Univ, Sch Med, Dept Pathol, Bedford, MA USA
[16] Boston Univ, Sch Med, Dept Psychiat, Bedford, MA USA
[17] Bedford Vet Affairs Med Ctr, Bedford, MA USA
[18] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA
[19] Ann Arbor Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Ann Arbor, MI USA
[20] Univ Glasgow, Fac Biomed & Life Sci, Div Mol Genet, Glasgow G11 6NU, Lanark, Scotland
[21] Univ Auckland, Dept Anat & Radiol, Auckland 1, New Zealand
基金
英国医学研究理事会;
关键词
D O I
10.1093/hmg/ddm133
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HID-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials.
引用
收藏
页码:1845 / 1861
页数:17
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