Reduced levels of dopamine and altered metabolism in brains of HPRT knock-out rats: a new rodent model of Lesch-Nyhan Disease

Meek, S. et al. (2016) Reduced levels of dopamine and altered metabolism in brains of HPRT knock-out rats: a new rodent model of Lesch-Nyhan Disease. Scientific Reports, 6, 25592. (doi: 10.1038/srep25592) (PMID:27185277) (PMCID:PMC4869022)

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.

• Item Type: Articles
• Additional Information: This work was supported by funding from the Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grants BB/J004316/1, BB/J004332/1: BBSRC Response mode grant BB/H012478/1, and European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement No. HEALTH-F4-2010-241504 (EURATRANS).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Weidt, Dr Stefan and Gloaguen, Mr Yoann
• Authors: Meek, S., Thomson, A., Sutherland, L., Sharp, M., Thomson, J., Bishop, V., Meddle, S., Gloaguen, Y., Weidt, S., Singh-Dolt, K., Buehr, M., Brown, H., Gill, A., and Burdon, T.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Scientific Reports
• Publisher: Nature Publishing Group
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2016 Nature Publishing Group
• First Published: First published in Scientific Reports 6:25592
• Publisher Policy: Reproduced under a Creative Commons License