title: A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease.
abstract: Huntington disease (HD) is an inherited progressive neurodegenerative disorder, characterized by motor, cognitive, and psychiatric deficits as well as neurodegeneration and brain atrophy beginning in the striatum and the cortex and extending to other subcortical brain regions. The genetic cause is an expansion of the CAG repeat stretch in the HTT gene encoding huntingtin protein (htt). Here, we generated an HD transgenic rat model using a human bacterial artificial chromosome (BAC), which contains the full-length HTT genomic sequence with 97 CAG/CAA repeats and all regulatory elements. BACHD transgenic rats display a robust, early onset and progressive HD-like phenotype including motor deficits and anxiety-related symptoms. In contrast to BAC and yeast artificial chromosome HD mouse models that express full-length mutant huntingtin, BACHD rats do not exhibit an increased body weight. Neuropathologically, the distribution of neuropil aggregates and nuclear accumulation of N-terminal mutant huntingtin in BACHD rats is similar to the observations in human HD brains. Aggregates occur more frequently in the cortex than in the striatum and neuropil aggregates appear earlier than mutant htt accumulation in the nucleus. Furthermore, we found an imbalance in the striatal striosome and matrix compartments in early stages of the disease. In addition, reduced dopamine receptor binding was detectable by in vivo imaging. Our data demonstrate that this transgenic BACHD rat line may be a valuable model for further understanding the disease mechanisms and for preclinical pharmacological studies.
authors.affiliation: Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Libo
authors.initials: L
authors.lastname: Yu-Taeger
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petrasch-Parwez
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Osmand
authors.forename: Adriana
authors.initials: A
authors.lastname: Redensek
authors.forename: Silke
authors.initials: S
authors.lastname: Metzger
authors.forename: Laura E
authors.initials: LE
authors.lastname: Clemens
authors.forename: Larry
authors.initials: L
authors.lastname: Park
authors.forename: David
authors.initials: D
authors.lastname: Howland
authors.forename: Carsten
authors.initials: C
authors.lastname: Calaminus
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Gu
authors.forename: Bernd
authors.initials: B
authors.lastname: Pichler
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Huu Phuc
authors.initials: HP
authors.lastname: Nguyen
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics*; D004435:Eating / Q000502:physiology; D020233:Gait Disorders, Neurologic / Q000523:psychology; D018628:Gene Dosage; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D007150:Immunohistochemistry; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D049268:Positron-Emission Tomography; D004856:Postural Balance / Q000502:physiology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger