Targeting NRF2 to protect against glycolytic dysfunction and MGO production in motor neurone disease

Details

Disruption to energy production and enhanced production of highly reactive substances that cause damage to cells, are known to contribute towards the death of motor neurones in motor neurone disease (MND). In healthy cells there is a protection pathway that senses disruption due to a build-up of a toxic bi-product of metabolism called methylglyoxal (MGO). MGO then activates Nrf-2 protection mechanisms that reduce free-radical production and restore MGO to non-toxic levels. We have evidence that parts of this pathway are disrupted in MND. Therefore, the project aims are to investigate energy metabolism in induced neuronal progenitor derived iAstrocytes reprogrammed from skin cells of MND and assess.

1. Levels of energy pathway intermediates and MGO levels. 

2. Levels of enzymes, involved in controlling MGO levels. 

3. Activation of the Nrf-2 mediated protection mechanisms involved in lowering free-radicals using small molecule activators of Nrf-2.

This will uncover mechanistically how a crucial cellular protection axis linking known disrupted MND pathways are altered in patient cells, potentially identifying targets for drug treatment.

The student will receive specialist training in iNPC cell culture and differentiation; 384 well fluorescent reporter assays; MS based metabolomics coupled with C-13 labelling; 96 well plate dose response assays; real time metabolic flux assays as well as basic lab techniques including western blotting, qRT-PCR and immunofluorescence. The PI group have expertise in astrocyte biology, metabolomics and Nrf-2 mechanisms and many of the techniques are already established. Moreover Dr Allen has strong established links with MND patient/public groups. Therefore, there is ample opportunity for the student to engage with people affected by MND. The student will receive training in lay and scientific presentations, we expect to disseminate our findings to local and national stakeholders. Moreover, we will present our findings at MND conferences including ENCALS and the ALS/MND Symposium. 

Interviews will likely be held in April. Students must be able to start by October 2023. 

Applications are open to students from both the UK and overseas, though we note that due to funding constraints the availability of positions for students with overseas fee status will be more limited. We anticipate competition for these studentships to be very intense. We would expect applicants to have an excellent undergraduate degree in a relevant discipline. We would also expect applicants to have completed or be undertaking a relevant master’s degree to a similar very high standard (or have equivalent research experience).