Transgenic rat model of Huntington's disease.
Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.
von Hörsten
Stephan
S
Department of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany. hoersten.stephan.von@mh-hannover.de
Schmitt
Ina
I
Nguyen
Huu Phuc
HP
Holzmann
Carsten
C
Schmidt
Thorsten
T
Walther
Thomas
T
Bader
Michael
M
Pabst
Reinhard
R
Kobbe
Philipp
P
Krotova
Jana
J
Stiller
Detlef
D
Kask
Ants
A
Vaarmann
Annika
A
Rathke-Hartlieb
Silvia
S
Schulz
Jörg B
JB
Grasshoff
Ute
U
Bauer
Ingrid
I
Vieira-Saecker
Ana Maria Menezes
AM
Paul
Martin
M
Jones
Lesley
L
Lindenberg
Katrin S
KS
Landwehrmeyer
Bernhard
B
Bauer
Andreas
A
Li
Xiao-Jiang
XJ
Riess
Olaf
O
D000818:Animals; D030801:Animals, Genetically Modified; D002467:Cell Nucleus / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005947:Glucose / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D019076:Transgenes; D019680:Trinucleotide Repeat Expansion; D014364:Tryptophan / Q000378:metabolism
D018076:DNA, Complementary; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014364:Tryptophan; D005947:Glucose