title: Metabolic disruption identified in the Huntington's disease transgenic sheep model.
abstract: Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease.
authors: Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand.
authors: Renee R
authors: RR
authors: Handley
authors: Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand.
authors: Suzanne J
authors: SJ
authors: Reid
authors: Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand.
authors: Stefano
authors: S
authors: Patassini
authors: Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development, Adelaide, SA 5350, Australia.
authors: Skye R
authors: SR
authors: Rudiger
authors: Research &Development, Livestock Improvement Corporation, Hamilton, 3240, New Zealand.
authors: Vladimir
authors: V
authors: Obolonkin
authors: Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development, Adelaide, SA 5350, Australia.
authors: Clive J
authors: CJ
authors: McLaughlan
authors: Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand.
authors: Jessie C
authors: JC
authors: Jacobsen
authors: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114, United States of America.
authors: James F
authors: JF
authors: Gusella
authors: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114, United States of America.
authors: Marcy E
authors: ME
authors: MacDonald
authors: Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand.
authors: Henry J
authors: HJ
authors: Waldvogel
authors: Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development, Adelaide, SA 5350, Australia.
authors: C Simon
authors: CS
authors: Bawden
authors: Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand.
authors: Richard L M
authors: RL
authors: Faull
authors: Centre for Brain Research, University of Auckland, Auckland, 1010, New Zealand.
authors: Russell G
authors: RG
authors: Snell
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D058070:Asymptomatic Diseases; D002531:Cerebellum / Q000378:metabolism* / Q000503:physiopathology; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D055442:Metabolome; D009044:Motor Cortex / Q000378:metabolism* / Q000503:physiopathology; D009928:Organ Specificity; D034561:Sheep, Domestic
chemical_list: D000596:Amino Acids; D005227:Fatty Acids