High Resolution 1H NMR-based Metabolomics Indicates a Neurotransmitter Cycling Deficit in Cerebral Tissue from a Mouse Model of Batten Disease

Department of Biochemistry, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2006; 280(52):42508-14. DOI: 10.1074/jbc.M507380200
Source: PubMed

ABSTRACT The neuronal ceroid lipofuscinoses (NCLs) constitute a range of progressive neurological disorders primarily affecting children.
Although six of the causative genes have been characterized, the underlying disease pathogenesis for this family of disorders
is unknown. Using a metabolomics approach based on high resolution 1H NMR spectroscopy of the cortex, cerebellum, and remaining regions of the brain in conjunction with statistical pattern recognition,
we report metabolic deficits associated with juvenile NCL in a Cln3 knock-out mouse model. Tissue from Cln3 null mutant mice aged 1–6 months was characterized by an increased glutamate concentration and a decrease in γ-amino butyric
acid (GABA) concentration in aqueous extracts from the three regions of the brain. These changes are consistent with the reported
altered expression of genes involved in glutamate metabolism in older mice and imply a change in neurotransmitter cycling
between glutamate/glutamine and the production of GABA. Further variations in myo-inositol, creatine, and N-acetyl-aspartate were also identified. These metabolic changes were distinct from the normal aging/developmental process.
Together, these changes represent the first documented pre-symptomatic symptoms of the Cln3 mouse at 1 month of age and demonstrate the versatility of 1H NMR spectroscopy as a tool for phenotyping mouse models of disease.

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Available from: Jonathan D Cooper, Aug 21, 2015
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    • "For example, 1 H-NMR has been used to uncover specific highly abundant metabolites (N-acetyl-aspartate, myo-inositol, glutamate , glutamine, creatine, choline, and GABA). Such studies have proven to be a key for the characterization of neurochemical and metabolic profiles relevant to brain health (Davidovic et al., 2011; Liu et al., 2013; Pears et al., 2005; Prabakaran et al., 2004; Tká c et al., 2004). Granting high reproducibility, the MR technologies are restricted by their low sensitivity, which hinders comprehensive pathologic assessments. "
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    Chemistry & Biology 11/2014; 21(11):1575-1584. DOI:10.1016/j.chembiol.2014.09.016 · 6.59 Impact Factor
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    • "quantitatively assay the entire range of metabolites present in a sample to characterize its overall biochemical state. Although MA sensitization has not yet been investigated using metabolomics, the platform has successfully identified biochemical signatures for other CNS pathologies including schizophrenia, Parkinson's and motor neuron disease (Bogdanov et al. 2008; Pears et al. 2005; Prabakaran et al. 2004). Thus, metabolomics offers the possibility of comprehensively mapping neurochemical profiles associated with MA-induced BSn, facilitating the identification of novel mechanisms , biomarkers and therapeutic targets. "
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    • "The term 'metabolomics' is defined as the study of ''the complete set of metabolites/low-molecular-weight intermediates , which are context dependent, varying according to the physiological, developmental or pathological state of the cell, tissue, organ or organism'' (Oliver 2003). Often, the terms metabolomics and metabonomics are used similarly in the literature and it is thus important to search for both terms, separately, while conducting a full literature search (Brindle et al. 2002; Leo et al. 2006; Pears et al. 2005; Psihogios et al. 2008; Rahmioglu et al. 2011; Rochfort et al. 2009; Verwaest et al. 2011; Viant et al. 2003; Wen et al. 2011; Qi et al. 2012; Hasim et al. 2012; Nevedomskaya et al. 2012; Zhang et al. 2012). However, Nicholson has distinguished between the two terms such that metabolomics is ''the measurement of metabolite concentrations and fluxes and secretion in cells and tissues in which there is a direct connection between the genetic activity, protein activity and the metabolic activity itself'' (Nicholson and Wilson 2003), whereas metabonomics is ''the quantitative measurement of the multivariate metabolic responses of multicellular systems to pathophysiological stimuli or genetic modification'' (Nicholson et al. 1999; Nicholson and Wilson 2003). "
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