MSACL 2019 US Abstract

Assessing the Effect of Nitisinone Induced Hypertyrosinaemia on Monoamine Neurotransmitters in a Murine Model of Alkaptonuria using Mass Spectrometry Imaging

Andrew S Davison (1,2), Nicole Strittmatter (3), Hazel Sutherland (2), Juliette Hughes (2), George Bou-Gharios (2), Anna M Milan (1,2), Richard Goodwin (3), James A Gallagher (2), Lakshminarayan R Ranganath (1,2)
(1) Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool & Broadgreen University Hospital Trust, Liverpool, UK (2) Institute of Ageing and Chronic Disease, Musculoskeletal Biology I, University of Liverpool, UK (3) Pathology, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK

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Andrew Davison (Presenter) University of Liverpool

Presenter Bio: Currently I am studying a NIHR funded PhD at the University of Liverpool. The focus of my research is to (i) investigate whether nitisinone induced hypertyrosinaemia observed in patients with Alkaptonuria affects neurotransmitter metabolism and (2) to assess the wider metabolic fate of tyrosine (beyond neurotransmitters) following treatment with nitisinone. My research involves the use of LC-QTOF-MS, LC-MS/MS, NMR and more recently DESI-MSI. Analysis is being carried out on patient urine and serum samples, as well as brain tissue and plasma from a murine model of Alkaptonuria. Before starting my PhD I had only used LC-MS/MS so it has been a steep learning curve as high resolution accurate mass spectrometry and mass spectrometry imaging are worlds apart from targeted LC-MS/MS based work. I am very excited by the potential of high resolution accurate mass spectrometry and mass spectrometry imaging in personalised healthcare both in supporting a clinical diagnosis, but also allowing more tailored treatments to be given to patients. It is a great time to be involved in what feels like a land mark change in how mass spectrometry can really make a difference to the way healthcare is delivered to patients.

Relevant Financial Disclosures (within past 24 months) No relevant financial relationship(s) to disclose. Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

Nitisinone induced hypertyrosinaemia is a concern in patients with Alkaptonuria (AKU). It has been suggested that hypertyrosinaemia may alter monoamine neurotransmitter metabolism, specifically dopamine and serotonin.
We report mass spectrometry imaging (MSI) of 2,4-diphenyl-pyranylium tetrafluoroborate derivatives of monoamine neurotransmitters in brain tissue from a murine model of AKU (BALBc HGD-/-) following treatment with nitisinone.
MSI showed tyrosine (9-fold, p=<0.0001) and tyramine (27-fold, p=0.0002) increased significantly following nitisinone. Dopamine, 3-methoxytyramine, noradrenaline, tryptophan, serotonin, and glutamate did not change.
This has significant implications for AKU patients as it suggests neurotransmitters are not altered following nitisinone therapy, only their precursors.