Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions.
We have serendipitously established a mouse that expresses an N-terminal human huntingtin (htt) fragment with an expanded polyglutamine repeat (approximately 120) under the control of the endogenous human promoter (shortstop). Frequent and widespread htt inclusions occur early in shortstop mice. Despite these inclusions, shortstop mice display no clinical evidence of neuronal dysfunction and no neuronal degeneration as determined by brain weight, striatal volume, and striatal neuronal count. These results indicate that htt inclusions are not pathogenic in vivo. In contrast, the full-length yeast artificial chromosome (YAC) 128 model with the identical polyglutamine length and same level of transgenic protein expression as the shortstop demonstrates significant neuronal dysfunction and loss. In contrast to the YAC128 mouse, which demonstrates enhanced susceptibility to excitotoxic death, the shortstop mouse is protected from excitotoxicity, providing in vivo evidence suggesting that neurodegeneration in Huntington disease is mediated by excitotoxic mechanisms.
Slow
Elizabeth J
EJ
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4.
Graham
Rona K
RK
Osmand
Alexander P
AP
Devon
Rebecca S
RS
Lu
Ge
G
Deng
Yu
Y
Pearson
Jacqui
J
Vaid
Kuljeet
K
Bissada
Nagat
N
Wetzel
Ronald
R
Leavitt
Blair R
BR
Hayden
Michael R
MR
D000704:Analysis of Variance; D000818:Animals; D001526:Behavioral Symptoms / Q000235:genetics / Q000503:physiopathology*; D001921:Brain / Q000473:pathology; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D019295:Computational Biology; D017931:DNA Primers; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D002479:Inclusion Bodies / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D045442:Rotarod Performance Test; D017422:Sequence Analysis, DNA
D017931:DNA Primers; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins