title: Further molecular characterisation of the OVT73 transgenic sheep model of Huntington's disease identifies cortical aggregates.
abstract: BACKGROUND
  Huntington's disease is a neurodegenerative disorder, typically with clinical manifestations in adult years, caused by an expanded polyglutamine-coding repeat in HTT. There are no treatments that delay or prevent the onset or progression of this devastating disease.
  
  
  OBJECTIVE
  In order to study its pre-symptomatic molecular progression and provide a large mammalian model for determining natural history of the disease and for therapeutic testing, we generated and previously reported on lines of transgenic sheep carrying a full length human HTT cDNA transgene, with expression driven by a minimal HTT promoter. We report here further characterization of our preferred line, OVT73.
  
  
  RESULTS
  This line reliably expresses the expanded human huntingtin protein at modest, but readily detectable levels throughout the brain, including the striatum and cortex. Transmission of the 73 unit glutamine coding repeat was relatively stable over three generations. At the first time-point of a longitudinal study, animals sacrificed at 6 months (7 transgenic, 7 control) showed reduced striatum GABAA α1 receptor, and globus pallidus leu-enkephalin immunoreactivity. Two of three 18 month old animals sacrificed revealed cortical neuropil aggregates. Furthermore, neuronal intranuclear inclusions were identified in the piriform cortex of a single 36 month old animal in addition to cortical neuropil aggregates.
  
  
  CONCLUSIONS
  Taken together, these data indicate that the OVT73 transgenic sheep line will progressively reveal early HD pathology and allow therapeutic testing over a period of time relevant to human patients.
authors: Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors: Suzanne J
authors: SJ
authors: Reid
authors: Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors: Stefano
authors: S
authors: Patassini
authors: Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors: Renée R
authors: RR
authors: Handley
authors: Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development, Adelaide, SA, Australia.
authors: Skye R
authors: SR
authors: Rudiger
authors: Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development, Adelaide, SA, Australia.
authors: Clive J
authors: CJ
authors: McLaughlan
authors: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA.
authors: Alex
authors: A
authors: Osmand
authors: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston.
authors: Jessie C
authors: JC
authors: Jacobsen
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors: A Jennifer
authors: AJ
authors: Morton
authors: IRBM Promidis, Pomezia, Italy.
authors: Andreas
authors: A
authors: Weiss
authors: Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors: Henry J
authors: HJ
authors: Waldvogel
authors: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston.
authors: Marcy E
authors: ME
authors: MacDonald
authors: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston.
authors: James F
authors: JF
authors: Gusella
authors: Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development, Adelaide, SA, Australia.
authors: C Simon
authors: CS
authors: Bawden
authors: Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors: Richard L M
authors: RL
authors: Faull
authors: Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors: Russell G
authors: RG
authors: Snell
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002540:Cerebral Cortex / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology*; D045586:Intranuclear Inclusion Bodies / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D034561:Sheep, Domestic / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
keywords: Huntington disease; neurosciences; ovis aries; sheep; transgenic animal