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  Combining pharmacology & AI to identify novel targets controlling proteostasis in neuronal cells


   London Interdisciplinary Biosciences Consortium (LIDo)

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  Dr P.J. McCormick, Dr Chris Jones, Dr C De Graaf, Dr G Osborne  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

To apply for this project please visit the LIDo website: https://www.lido-dtp.ac.uk/apply

Neurodegenerative diseases (NDs) are debilitating conditions linked with aberrant health aging, a key BBSRC focus. Whilst the molecular origins for NDs are multiple, the dysregulation of protein homeostasis -or proteostasis- network, involving protein synthesis, folding & trafficking, is central to the progression of NDs. This results in cellular stresses leading to cell death. At the molecular level, it is assumed that the accumulation of pathological aggregates result from non-physiological aggregation of proteins prone to misfolding, accumulating due to age-related deficits in proteostatic systems, including the proteasome, mitochondrial dysfunction, stress & autophagic system.

Metabolic regulation & neurons. The metabolic state of the cell affects the capacity to produce enough energy to maintain proteostasis acting as a trigger for the formation of a stress response. Multiple pathways can adjust the cells’ metabolic state, illustrating its importance, including the unfolded protein response (UPR), mitochondrial quality control in the form of the mitochondrial UPR (UPRMT) & energy regulation via mitochondrial number, direct mitochondrial – ER & nuclear signalling, as well as the proteasome system, & the granulophagy-autophagy-ferritinophagy-lysosomal pathways. If one of these processes fails, cell death is programmed through apoptosis, necroptosis or ferroptosis. Thus, signalling pathways linking the cell’s metabolic state & mitochondrial function with cytoplasmic quality control are central to proteostasis control.

Neurotransmitters, proteostasis & cell metabolism in NDs: Many therapeutic approaches to NDs have focused on addressing imbalances in either neurotransmitter levels (dopamine in PD or glutamate in AD) or in receptors for a neurotransmitter or associated receptors (eg. sigma-1 in ALS) . It is known that targeting different GPCRs can directly modulate autophagy which in some cases is driven by Rab GTPases & others via an mTOR driven pathway. In addition, inflammation is a driver of cell stress, & reducing inflammation is a major goal in combating many NDs. Thus, understanding the relationship between key neurotransmitters, their cognate receptors & their influence on proteostasis will be essential to identify new leads for targeted therapeutic approaches.

Our hypothesis is that although each ND involves distinct culprit proteins; common regulatory nodes exist driving changes in protein homeostasis.

Our aim is to use iPS cell models of NDs to identify targets for modulating proteostasis in neuronal cells. We will achieve this by harnessing Sosei Heptares’ GPCR drug discovery platform coupled with GPCR-targeted chemogenomic libraries.

The student will become well versed in Cell Biology, Pharmacology, and Computational Biology. The project will be closely coordinated between Queen Mary University of London and Sosei Heptares (https://soseiheptares.com/) in Cambridge with a significant period spent at Sosei Heptares.

To apply for this project please visit the LIDo website: https://www.lido-dtp.ac.uk/apply


Biological Sciences (4) Chemistry (6) Mathematics (25) Medicine (26)

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £17,609.
LIDo has a maximum of 11 fully funded opportunities for students eligible for overseas fees.

References

Bourdenx, M., Martín-Segura, A., Scrivo, A., Rodriguez-Navarro, J.A., Kaushik, S., Tasset, I., Diaz, A., Storm, N.J., Xin, Q., Juste, Y.R., et al. (2021). Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell.
Cheng, J., North, B.J., Zhang, T., Dai, X., Tao, K., Guo, J., and Wei, W. (2018). The emerging roles of protein homeostasis-governing pathways in Alzheimer’s disease. Aging Cell 17, e12801.
Kaushik, S., and Cuervo, A.M. (2015). Proteostasis and aging. Nat Med 21, 1406–1415.
Kurtishi, A., Rosen, B., Patil, K.S., Alves, G.W., and Møller, S.G. (2019). Cellular Proteostasis in Neurodegeneration. Mol Neurobiol 56, 3676–3689.
Moehle, E.A., Shen, K., and Dillin, A. (2019). Mitochondrial proteostasis in the context of cellular and organismal health and aging. J. Biol. Chem. 294, 5396–5407.