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The metabolomics of alpha-synuclein (SNCA) gene deletion and mutation in mouse brain

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Abstract

Using a novel metabolomics approach the current study aimed to further characterize the functional attributes of alpha-synuclein that mediate its involvement in neurodegeneration. The metabolic profiles of alpha-synuclein knockout and A53T mutant overexpressing mouse brains were studied using proton nuclear magnetic resonance (1H NMR) and liquid chromatography mass spectrometry (LC/MS). Gene deletion and mutation were both associated with significant alterations in brain energy metabolism when compared with their respective wild-type controls. These changes indicated deficiencies in key metabolic pathways, including the tricarboxylic acid cycle, and significant differences in the concentrations of small molecules including adenine nucleotides, taurine, NAD+ and glutamine. Analysis of the metabolic pathways affected by both knockout and mutation further indicated involvement of alpha-synuclein in metabolic pathways of energy metabolism, cellular redox status and glycerophospholipid metabolism. As such, our data identify novel functions of alpha-synuclein, validate previous reports describing its contribution to energy metabolism and lipid synthesis and support the use of metabolomic analysis as a fundamental technique in defining the effect of protein expression and mutation in genetic models.

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Acknowledgments

The authors thank Dr. Reza Salek for helpful comments and advice. Funding sources include the NHMRC (Project Grant and Career Development Fellowship to TD) and the Tasmanian Masonic Centenary Medical Research Foundation. We thank Dr. Tim De Meyer for his donation of Matlab scripts.

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Authors and Affiliations

  1. Menzies Research Institute Tasmania, University of Tasmania, Private Bag 23, Hobart, TAS, 7000, Australia

    Ruth E. Musgrove & Tracey C. Dickson

  2. Central Science Laboratory, University of Tasmania, Hobart, TAS, Australia

    James Horne & Richard Wilson

  3. Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, TAS, Australia

    Anna E. King

  4. Centre of Human and Aerospace Physiological Sciences, King’s College London, London, ON, UK

    Lindsay M. Edwards

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  1. Ruth E. Musgrove
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  2. James Horne
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  3. Richard Wilson
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  4. Anna E. King
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  5. Lindsay M. Edwards
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  6. Tracey C. Dickson
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Correspondence to Tracey C. Dickson.

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Lindsay M. Edwards and Tracey C. Dickson are the joint senior authors.

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Musgrove, R.E., Horne, J., Wilson, R. et al. The metabolomics of alpha-synuclein (SNCA) gene deletion and mutation in mouse brain. Metabolomics 10, 114–122 (2014). https://doi.org/10.1007/s11306-013-0561-6

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  • DOI: https://doi.org/10.1007/s11306-013-0561-6

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