Overview
This project will explore the contribution of the tyrosine metabolic pathway to oxidative stress. Special emphasis will be placed on disorders of tyrosine metabolism including the inherited condition alkaptonuria, which has recently been linked with Parkinson’s disease. You will apply a range of advanced techniques in biochemistry and redox biology to characterise the link between exposure to tyrosine metabolites and oxidative stress in cell and mouse models. This novel area of research has potential to elucidate new mechanisms of neurodegeneration and will have important implications for treatment of inherited disorders of tyrosine metabolism.
About this opportunity
We are seeking a motivated researcher to work on a pioneering project investigating the role of oxidative stress associated with tyrosine metabolism.
Our cells are constantly exposed to stress in various forms. A major group of stressors is those that induce oxidative damage to cells and their constituents, including UV radiation from sunlight and environmental pollutants. The project will explore the novel idea that that molecules associated with the amino acid tyrosine are previously unrecognised sources of oxidative stress. Dr Norman and colleagues have discovered that a specific breakdown product of tyrosine is a direct source of free radicals1. In patients with a genetic condition known as alkaptonuria (AKU) that causes lifelong exposure to this oxidative molecule if untreated, there is marked alteration to antioxidant pathways and greater incidence of devastating degenerative disorders including osteoarthritis and Parkinson’s disease2,3,4.
Phenylalanine-tyrosine metabolism is an essential biological pathway. This pathway is the major degradation route of the amino acids phenylalanine and tyrosine and the source of molecules with essential functions in multiple organ systems, including melanin, neurotransmitters such as dopamine, and thyroid hormones. Defining the contribution of this pathway to systemic oxidative damage will be a major breakthrough with potential to reveal new disease mechanisms and therapeutic targets.
This project aims to assess the effects of chronic exposure to supraphysiological concentrations of tyrosine and its metabolite products on cell function. Key emphasis will be placed on readouts associated with oxidative stress as a potential common disease mechanism across the various disorders of tyrosine metabolism. You will benefit from the group’s long-standing expertise in tyrosine metabolism and access to world-class resources including advanced biochemical analytical techniques for metabolite and neurotransmitter analysis.
EXPERIMENTAL APPROACH:
The candidate will establish cell-based systems to model the effects of chronic exposure to tyrosine pathway metabolites in target organs. Readouts from these in vitro systems will include cell viability, profiling of established markers of oxidative stress, autophagy/mitophagy, cellular energetics (Seahorse analysis) and data from ‘omics analyses including transcriptomics, proteomics and metabolomics.
We are particularly interested in the effects of HGA and tyrosine on neuronal function to shed light on the apparent links between AKU/tyrosinemia and Parkinson’s disease. In addition to the above readouts, the candidate will develop analytical techniques for measurement of neurotransmitters using advanced LC/MS instrumentation available in our laboratory.
There is also potential to explore phenotypes in a new mouse model of AKU (Hgd gene knockout) combined with knockout of the Nrf2 gene, a master regulator of the antioxidant response. This double transgenic mouse line has been generated in our laboratory and various tissues and biofluids have been collected following ageing of these mice up to one year. There is the opportunity to characterise the phenotype of this mouse line (e.g. neurological, oxidative, metabolic) to complement the in vitro aspect of the project.
NOVELTY AND POTENTIAL IMPACT:
Your research will provide the first systematic exploration of oxidative stress in experimental models of tyrosine metabolic dysregulation. The project has the potential to reveal new pathological mechanisms of disease in common degenerative disorders including Parkinson’s disease. Our close partnership with multiple clinical groups working on target tyrosine metabolic disorders will maximise the future clinical potential of the research.