A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration.
We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.
Hodgson
J G
JG
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
Agopyan
N
N
Gutekunst
C A
CA
Leavitt
B R
BR
LePiane
F
F
Singaraja
R
R
Smith
D J
DJ
Bissada
N
N
McCutcheon
K
K
Nasir
J
J
Jamot
L
L
Li
X J
XJ
Stevens
M E
ME
Rosemond
E
E
Roder
J C
JC
Phillips
A G
AG
Rubin
E M
EM
Hersch
S M
SM
Hayden
M R
MR
D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000473:pathology; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics*; D003342:Corpus Striatum / Q000473:pathology*; D003593:Cytoplasm / Q000473:pathology; D004195:Disease Models, Animal; D004594:Electrophysiology; D004622:Embryo, Mammalian / Q000502:physiology; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins