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MSc by Research programme - ADP-ribosylation in dementia and motor neuron disease


School of Life Sciences

Dundee United Kingdom Biochemistry Cell Biology Genetics Molecular Biology Neuroscience Structural Biology

About the Project

ADP-ribosylation is a fundamental posttranslational modification where ADP-ribose is linked on to target proteins by ADP-ribose transferases and removed by the ADP-ribose hydrolases. Emerging data implicate ADP-ribosylation in maintaining the health of the nervous system; mutations in the genes that encode the enzymes that reverse ADP-ribosylation cause neurodegenerative disease in humans and pharmacological inhibition of the ADP-ribose transferases is therapeutically beneficial in various cellular and animal models of human neurodegenerative diseases such as stroke, Parkinson’s disease and motor neuron disease (reviewed in 1). This suggests that ADP-ribosylation regulates key proteins involved in brain aging, however what these proteins are and how they are regulated by ADP-ribosylation is unknown. To elucidate the proteins and underlying mechanisms that regulate brain aging, the student will use an interdisciplinary approach that combines genetics of the fruit fly with molecular and cellular approaches to determine the role of nuclear ADP-ribosylation in the ageing and diseased nervous system of the fly (AIM1) and in human cells (AIM2).

At the end of this project the student will have identified novel aspects of ADP-ribosylation in the normal and diseased nervous system. 

Please see our website for further details and how to apply - https://www.dundee.ac.uk/study/pgr/life-sciences-msc-research/


References

 Background reading 1-6
[1] *McGurk L, Rifai O, and *Bonini NM. TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2. J Cell Sci. 2020 May 14
[2] McGurk, L., Rifai, O. M., and Bonini, N. M. (2019) Poly(ADP-Ribosylation) in Age- Related Neurological Disease, Trends Genet 35, 601-613.
[3] McGurk, L., Mojsilovic-Petrovic, J., Van Deerlin, V. M., Shorter, J., Kalb, R. G., Lee, V. M., Trojanowski, J. Q., Lee, E. B., and Bonini, N. M. (2018) Nuclear poly(ADP- ribose) activity is a therapeutic target in amyotrophic lateral sclerosis, Acta neuropathologica communications 6, 84-95.
[4] McGurk, L., Gomes, E., Guo, L., Mojsilovic-Petrovic, J., Tran, V., Kalb, R. G., Shorter, J., and Bonini, N. M. (2018) Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization, Molecular cell 71, 703-717 e709.
[5] McGurk, L., Gomes, E., Guo, L., Shorter, J., and Bonini, N. (2018) Poly(ADP-ribose) engages the TDP-43 nuclear-localization sequence to regulate granulo- filamentous aggregation, Biochemistry 57, 6923-6926
[6] McGurk, L., Berson, A., and Bonini, N. M. (2015) Drosophila as an In Vivo Model for Human Neurodegenerative Disease, Genetics 201, 377-402.

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