Studentship | Discovery of novel mitochondrial and organelle mechanisms underlying Parkinson’s disease

ASAP
Northwood
Project with

Parkinson’s disease (PD) is a movement disorder that is now the fastest growing neurological disorder in the world. Despite much research the disease is incurable and there are no treatments that can slow the disease down. The discovery of genetic mutations in rare familial forms has transformed our understanding of the origins of PD but the function of these genes is poorly understood. Mutations in PTEN-induced kinase 1 (PINK1) cause autosomal recessive PD. PINK1 is unique amongst all protein kinases due to the presence of a mitochondrial targeting domain that localises it to mitochondria. Our lab has made a number of groundbreaking discoveries and uncovered mechanisms that explain how PINK1 and Parkin activation lead to the removal of damaged mitochondria by mitophagy. Excitingly based on this research there are now Phase I trials for PD patients using molecules that boost PINK1-dependent mitophagy. However, there remain many outstanding questions on the regulation of PINK1 and its downstream biology that may lead to new diagnostic and therapeutic strategies to tackle PD. These include the molecular mechanism by which PINK1 senses mitochondrial damage; the role of other PINK1 substrates including Rab GTPases; how PINK1 mutations impacts other organelles including lysosomes and endosomes; the roles of the PINK1 pathway in the brain; and identification of regulators and PINK1-independent mechanisms that may compensate for loss of PINK1 in cells. Our lab uses a multidisciplinary approach to address these questions and the successful student will gain exposure and training in many state-of-the-art methods including mass spectrometry / proteomic technologies; CRISPR/Cas9 technologies; cutting edge methods to isolate organelles, and tissue culture using human iPSC-derived neurons or mice-based analysis. The lab also collaborates with many labs around the world and is actively involved in public engagement. In addition to training and development opportunities within the MRC Protein Phosphorylation & Ubiquitylation Unit and Dundee , the Muqit lab is a member of the EMBO Young Investigator Network (https://people.embo.org/profile/miratul-muqit) and students have opportunities to attend EMBO PhD courses and workshops. The lab is also part of the innovative global Aligning Science Across Parkinson’s (ASAP) initiative (https://parkinsonsroadmap.org/research-network/pd-functional-genomics/#) that also enables students to experience cutting edge development opportunities.

References

  1. Bagnoli, E., Lin, Y-U., Burel, S., et al. (2024) Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain. bioRxiv 2024.06.11.598416; doi: https://doi.org/10.1101/2024.06.11.598416

  2. Raimi, O.G., Ojha, H., Ehses, K., et al. (2024) Mechanism of human PINK1 activation at the TOM complex in a reconstituted system. Science Adv. 10: eadn7191.

  3. Stevens, M.U., Croteau, N., Eldeeb, et al. (2023) Structure-based design and characterization of Parkin activating mutations. Life Sci Alliance 6: e202201419

  4. Antico, O., Ordureau, A., Stevens, et al. (2021) Global ubiquitylation analysis of mitochondria in primary neurons identifies physiological Parkin targets following activation of PINK1. Science Adv 7: eabj0722

Application Procedure

To apply for any of our PhD projects, please complete the following application

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When completing the application, we will ask you to upload your CV and a cover letter explaining why you have chosen to apply to MRC PPU.

The closing date for applications is 15th January 2025. Applications from overseas students are welcome.

If you have any questions or need to get in touch with us, please email us at mrcppu-phd-admin@dundee.ac.uk.