Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease.
In postmortem Huntington's disease brains, mutant htt is present in both nuclear and cytoplasmic compartments. To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization or nuclear export signal sequences have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus is sufficient for and dramatically accelerates the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein is sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. However, our data suggest that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression.
Benn
Caroline L
CL
King's College London, Medical and Molecular Genetics, GKT School of Medicine, UK.
Landles
Christian
C
Li
He
H
Strand
Andrew D
AD
Woodman
Ben
B
Sathasivam
Kirupa
K
Li
Shi-Hua
SH
Ghazi-Noori
Shabnam
S
Hockly
Emma
E
Faruque
Syed M N N
SM
Cha
Jang-Ho J
JH
Sharpe
Paul T
PT
Olson
James M
JM
Li
Xiao-Jiang
XJ
Bates
Gillian P
GP
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D045442:Rotarod Performance Test; D014158:Transcription, Genetic; D019076:Transgenes / Q000235:genetics
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; C097188:polyglutamine