Transgenic rat model of Huntington's disease

被引:257
作者
von Hörsten, S
Schmitt, I
Nguyen, HP
Holzmann, C
Schmidt, T
Walther, T
Bader, M
Pabst, R
Kobbe, P
Krotova, J
Stiller, D
Kask, A
Vaarmann, A
Rathke-Hartlieb, S
Schulz, JB
Grasshoff, U
Bauer, I
Vieira-Saecker, AMM
Paul, M
Jones, L
Lindenberg, KS
Landwehrmeyer, B
Bauer, A
Li, XJ
Riess, O
机构
[1] Hannover Med Sch, Dept Funct & Appl Anat, D-30625 Hannover, Germany
[2] Ruhr Univ Bochum, Dept Human Mol Genet, D-4630 Bochum, Germany
[3] Univ Rostock, Childrens Hosp, Dept Med Genet, Rostock, Germany
[4] Univ Tubingen, Dept Med Genet, Tubingen, Germany
[5] Free Univ Berlin, Hosp Benjamin Franklin, Dept Cardiol, D-1000 Berlin, Germany
[6] Max Delbruck Ctr Mol Med, Berlin, Germany
[7] Leibniz Inst Neurobiol, Dept Noninvas Imaging, Magdeburg, Germany
[8] Univ Tartu, Dept Pharmacol, EE-50090 Tartu, Estonia
[9] Univ Tubingen, Dept Neurol, D-7400 Tubingen, Germany
[10] Free Univ Berlin, Hosp Benjamin Franklin, Inst Pharmakol & Toxicol, D-1000 Berlin, Germany
[11] Univ Wales Coll Cardiff, Coll Med, Inst Med Genet, Cardiff CF1 3NS, S Glam, Wales
[12] Univ Ulm, Dept Neurol, D-7900 Ulm, Germany
[13] Inst Med, Res Ctr, Julich, Germany
[14] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA
关键词
D O I
10.1093/hmg/ddg075
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:617 / 624
页数:8
相关论文
共 41 条
[1]   GLYCOLYSIS-INDUCED DISCORDANCE BETWEEN GLUCOSE METABOLIC RATES MEASURED WITH RADIOLABELED FLUORODEOXYGLUCOSE AND GLUCOSE [J].
ACKERMANN, RF ;
LEAR, JL .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1989, 9 (06) :774-785
[2]   BEHAVIORAL PATHOLOGY INDUCED BY REPEATED SYSTEMIC INJECTIONS OF 3-NITROPROPIONIC ACID MIMICS THE MOTORIC SYMPTOMS OF HUNTINGTONS-DISEASE [J].
BORLONGAN, CV ;
KOUTOUZIS, TK ;
FREEMAN, TB ;
CAHILL, DW ;
SANBERG, PR .
BRAIN RESEARCH, 1995, 697 (1-2) :254-257
[3]   Postnatal lipopolysaccharide-induced illness predisposes to periodontal disease in adulthood [J].
Breivik, T ;
Stephan, M ;
Brabant, GE ;
Straub, RH ;
Pabst, R ;
von Hörsten, S .
BRAIN BEHAVIOR AND IMMUNITY, 2002, 16 (04) :421-438
[4]   CHRONIC MITOCHONDRIAL ENERGY IMPAIRMENT PRODUCES SELECTIVE STRIATAL DEGENERATION AND ABNORMAL CHOREIFORM MOVEMENTS IN PRIMATES [J].
BROUILLET, E ;
HANTRAYE, P ;
FERRANTE, RJ ;
DOLAN, R ;
LEROYWILLIG, A ;
KOWALL, NW ;
BEAL, MF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (15) :7105-7109
[5]   THE QUINOLINIC ACID HYPOTHESIS IN HUNTINGTON CHOREA [J].
BRUYN, RPM ;
STOOF, JC .
JOURNAL OF THE NEUROLOGICAL SCIENCES, 1990, 95 (01) :29-38
[6]  
Carter RJ, 1999, J NEUROSCI, V19, P3248
[7]   Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests [J].
Crawley, JN .
BRAIN RESEARCH, 1999, 835 (01) :18-26
[8]   Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation [J].
Davies, SW ;
Turmaine, M ;
Cozens, BA ;
DiFiglia, M ;
Sharp, AH ;
Ross, CA ;
Scherzinger, E ;
Wanker, EE ;
Mangiarini, L ;
Bates, GP .
CELL, 1997, 90 (03) :537-548
[9]   Striatal transplantation in a transgenic mouse model of Huntington's disease [J].
Dunnett, SB ;
Carter, RJ ;
Watts, C ;
Torres, EM ;
Mahal, A ;
Mangiarini, L ;
Bates, G ;
Morton, AJ .
EXPERIMENTAL NEUROLOGY, 1998, 154 (01) :31-40
[10]   Striking changes in anxiety in Huntington's disease transgenic mice [J].
File, SE ;
Mahal, A ;
Mangiarini, L ;
Bates, GP .
BRAIN RESEARCH, 1998, 805 (1-2) :234-240