title: Reduced levels of dopamine and altered metabolism in brains of HPRT knock-out rats: a new rodent model of Lesch-Nyhan Disease.
abstract: Lesch-Nyhan disease (LND) is a severe neurological disorder caused by loss-of-function mutations in the gene encoding hypoxanthine phosphoribosyltransferase (HPRT), an enzyme required for efficient recycling of purine nucleotides. Although this biochemical defect reconfigures purine metabolism and leads to elevated levels of the breakdown product urea, it remains unclear exactly how loss of HPRT activity disrupts brain function. As the rat is the preferred rodent experimental model for studying neurobiology and diseases of the brain, we used genetically-modified embryonic stem cells to generate an HPRT knock-out rat. Male HPRT-deficient rats were viable, fertile and displayed normal caged behaviour. However, metabolomic analysis revealed changes in brain biochemistry consistent with disruption of purine recycling and nucleotide metabolism. Broader changes in brain biochemistry were also indicated by increased levels of the core metabolite citrate and reduced levels of lipids and fatty acids. Targeted MS/MS analysis identified reduced levels of dopamine in the brains of HPRT-deficient animals, consistent with deficits noted previously in human LND patients and HPRT knock-out mice. The HPRT-deficient rat therefore provides a new experimental platform for future investigation of how HPRT activity and disruption of purine metabolism affects neural function and behaviour.
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Meek
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Thomson
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Linda
authors.initials: L
authors.lastname: Sutherland
authors.affiliation: Central Bioresearch Services, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, Scotland.
authors.forename: Matthew G F
authors.initials: MG
authors.lastname: Sharp
authors.affiliation: Central Bioresearch Services, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, Scotland.
authors.forename: Julie
authors.initials: J
authors.lastname: Thomson
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Bishop
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Simone L
authors.initials: SL
authors.lastname: Meddle
authors.affiliation: Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Campus, Bearsden, G61 1QH, Scotland.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Gloaguen
authors.affiliation: Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Campus, Bearsden, G61 1QH, Scotland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Weidt
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Karamjit
authors.initials: K
authors.lastname: Singh-Dolt
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Mia
authors.initials: M
authors.lastname: Buehr
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Brown
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Gill
authors.affiliation: The Roslin Institute and R(D)VS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland.
authors.forename: Tom
authors.initials: T
authors.lastname: Burdon
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency / Q000235:genetics; D007926:Lesch-Nyhan Syndrome / Q000235:genetics / Q000378:metabolism*; D008297:Male; D055432:Metabolomics / Q000379:methods; D018345:Mice, Knockout; D009154:Mutation; D011685:Purine Nucleotides / Q000378:metabolism; D055647:Rats, Transgenic; D012377:Rodentia; D053719:Tandem Mass Spectrometry
chemical_list: D011685:Purine Nucleotides; D007041:Hypoxanthine Phosphoribosyltransferase; D004298:Dopamine