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.
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 HD-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.
Kuhn
Alexandre
A
Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Goldstein
Darlene R
DR
Hodges
Angela
A
Strand
Andrew D
AD
Sengstag
Thierry
T
Kooperberg
Charles
C
Becanovic
Kristina
K
Pouladi
Mahmoud A
MA
Sathasivam
Kirupa
K
Cha
Jang-Ho J
JH
Hannan
Anthony J
AJ
Hayden
Michael R
MR
Leavitt
Blair R
BR
Dunnett
Stephen B
SB
Ferrante
Robert J
RJ
Albin
Roger
R
Shelbourne
Peggy
P
Delorenzi
Mauro
M
Augood
Sarah J
SJ
Faull
Richard L M
RL
Olson
James M
JM
Bates
Gillian P
GP
Jones
Lesley
L
Luthi-Carter
Ruth
R
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger