Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice.
Huntington's disease (HD) is caused by an expanded N-terminal glutamine tract that endows huntingtin with a striatal-selective structural property ultimately toxic to medium spiny neurons. In precise genetic models of juvenile HD, HdhQ92 and HdhQ111 knock-in mice, long polyglutamine segments change huntingtin's physical properties, producing HD-like in vivo correlates in the striatum, including nuclear localization of a version of the full-length protein predominant in medium spiny neurons, and subsequent formation of N-terminal inclusions and insoluble aggregate. These changes show glutamine length dependence and dominant inheritance with recruitment of wild-type protein, critical features of the altered HD property that strongly implicate them in the HD disease process and that suggest alternative pathogenic scenarios: the effect of the glutamine tract may act by altering interaction with a critical cellular constituent or by depleting a form of huntingtin essential to medium spiny striatal neurons.
Wheeler
V C
VC
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
White
J K
JK
Gutekunst
C A
CA
Vrbanac
V
V
Weaver
M
M
Li
X J
XJ
Li
S H
SH
Yi
H
H
Vonsattel
J P
JP
Gusella
J F
JF
Hersch
S
S
Auerbach
W
W
Joyner
A L
AL
MacDonald
M E
ME
D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry; D005973:Glutamine / Q000235:genetics* / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D007106:Immune Sera / Q000737:chemistry; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016254:Mutagenesis, Insertional; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D012995:Solubility
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007106:Immune Sera; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D005973:Glutamine; C097188:polyglutamine