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Mitochondrial toxicity in Drosophila models of neurodegenerative diseases


Project Description

The MRC Toxicology Unit is a leading international research institute within the School of Biological Sciences in the University of Cambridge. The Unit is currently located in Leicester and will be relocating to Cambridge during 2020. Candidates will therefore be undertaking the first part of their PhD at the Unit’s current premises in Leicester. The research environment provides state of the art research facilities, with excellent opportunities for collaborative interaction within a vibrant community at the University of Cambridge.

Dr. Miguel Martins is Head of the research group focusing on mitochondria and cell death regulation following toxic injury, with particular interest in toxicity associated with neurodegenerative disease. For further information, please go to (https://www.mrc-tox.cam.ac.uk/staff/dr-l-miguel-martins).

Dr. Martins is seeking a PhD student with a strong interest in cell biology and Drosophila as a model organism to lead a project on the impact of mitochondrial toxicity on cellular and organ dysfunction. The toxic ’Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Aβ protofibril formation. A Drosophila model of Aβ toxicity has been achieved by creating transgenic flies expressing ‘Arctic’ mutant (Glu22Gly) Aβ peptides (1-42) in neurons (Crowther et al., 2005). Human carriers of this pathogenic amyloid precursor protein mutation, located within the Aβ sequence develop AD, involving rapid protofibril formation (Nilsberth et al., 2001).

Mitochondria are involved in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease, and the majority of the metabolic processes in which mitochondria are involved are known to be affected in neurodegeneration (Schon and Przedborski, 2011).

We have characterised the metabolic signature of flies expressing toxic Aβ-Arc and detected significant changes in the co-enzyme nicotinamide adenine dinucleotide (NAD+), involved in mitochondrial metabolism.
The objective of this project is exploring the neuroprotective potential of enhancing nucleotide metabolism in fly models of AD associated with Aβ toxicity.

This studentship is for four years commencing October 2019 with an annual stipend of £15,000 (tax free).

It is recommended that you contact the supervisor prior to making your formal application:

More information about our research can be found at the lab’s website:

https://www.mrc-tox.cam.ac.uk/research/l-m-martins-programme


Funding Notes

Candidates must expect to obtain qualifications at the level of a first-class or 2.1 Honours Degree in a biological science or related discipline.

Full funding is available to UK and EU applicants only.

References

The key research papers related to this project are:

• Lehmann, S., Costa, A.C., Celardo, I., Loh, S.H., and Martins, L.M. (2016). Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson's disease. Cell Death Dis 7, e2166.
• Lehmann, S., Loh, S.H., and Martins, L.M. (2017a). Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease. Biol Open 6, 141-147
• Tufi, R., Gandhi, S., de Castro, I.P., Lehmann, S., Angelova, P.R., Dinsdale, D., Deas, E., Plun-Favreau, H., Nicotera, P., Abramov, A.Y., et al. (2014). Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson's disease. Nat Cell Biol 16, 157-166.

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