Professor Miratul MuqitFMedSci FRSE

Parkinson’s disease is a progressive disorder of movement and coordination due to the specific loss of dopaminergic neurons in the brain. There are no medicines that can slow or halt the disease process largely due to a lack of understanding of the fundamental mechanisms. Spectacular advances in genetics have identified 13 genes that are mutated in familial forms of the disease and nearly 90 gene variants that increase susceptibility to sporadic disease. Understanding the regulation and signalling networks in which these genes reside is likely to elaborate new knowledge on the key cellular pathways that are vital for maintaining neuronal integrity and health. It may also lead to the development of novel approaches to better diagnose and treat Parkinson’s.

My lab studies the protein kinase, PTEN-induced kinase 1 (PINK1) in which loss of function mutations cause Parkinson’s disease. We are interested in understanding how PINK1 is regulated and how mutations lead to neurodegeneration. Studies to date indicate that PINK1 is a master regulator of a mitochondrial damage response pathway that exists in many different cell types including neurons. Under healthy conditions PINK1 is inactive, however, upon selective mitochondrial stress, PINK1 is activated and stimulates the removal of damaged mitochondrial via autophagy (termed mitophagy) thereby promoting cell survival.

My lab found that PINK1 phosphorylates ubiquitin and Parkin at a Ser residue (Serine 65) located within a conserved fold of ubiquitin and the ubiquitin-like domain of Parkin. We also determined the mechanism of activation of Parkin E3 ligase activity by phosphorylated-ubiquitin. We were able to demonstrate the relevance of our findings to the pathogenesis of Parkinson’s through analysis of a Parkin Ser65Ala knock-in mouse and the discovery of rare Parkinson’s patients harbouring mutations of the Parkin Ser65 site. In collaboration with the van Aalten lab, we solved the first crystal structure of PINK1 using an insect orthologue that has revealed the mechanisms of how disease mutations impact on PINK1 activity. Collectively our work has stimulated interest amongst industry to develop small molecule activators of Parkin and PINK1.

We have also found that PINK1 stimulates the phosphorylation of a subset of Rab GTPases (Rab1B, 8A, 8B and 13) at a conserved Ser residue (Ser111) that lies within the SF3 motif. PINK1 dependent phosphorylation of Rabs disrupts its ability to interact with its cognate guanine exchange factor, Rabin8, and more recently we have found that phosphorylation impairs the ability of another Parkinson’s associated kinase LRRK2 to phosphorylate Thr72 within the Switch II domain.

Outstanding questions include understanding how PINK1 is activated upon mitochondrial depolarisation and determining novel regulatory proteins required for PINK1 activation. We are establishing robust methods to study PINK1 signalling in neurons and defining the downstream biology in these cell types. We are also investigating the mechanisms by which Rab GTPases are regulated by PINK1 activation.

Research Impact

Our research has stimulated interest in exploiting phosphorylation and ubiquitylation mechanisms in Parkinson’s disease for drug discovery. We have active collaborations with industry including Astex Pharmaceuticals and Mitokinin Inc.

We also collaborate with the pharmaceutical industry via the Division of Signal Transduction Therapy collaboration with Boehringer Ingelheim, GlaxoSmithKline, and Merck Serono with the research outputs from my group contributing to accelerating the development of company drug development programmes through access to research data and reagents.

We actively contribute to many public engagement projects including working with school children through the MRC-PPU programme and also artists. We also are leading contributors to the collaboration termed the “Edinburgh-Dundee-Parkinson's-Research-Initiative” that promotes interactions between Parkinson’s researchers, clinicians and patients based in the East of Scotland.

Selected Publications

1. Bagnoli, E., Lin Y-E., Burel, S., Jaimon, E., Antico, O., Themistokleous C., Nikoloff, J.M., Morella, I., Watzlawik J.O., Fiesel, F.C., Springer, W., Tonelli, F., Brooks, S.P., Dunnett, S.B., Brambilla, R., Alessi, D.R., Pfeffer, S.R., Muqit, M.M. (2025) Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain. bioRxiv 2024.06.11.598416. In press Proc Natl Acad Sci
2. Raimi, O.G., Ojha, H., Ehses, K., Dederer, V., Lange, S.M., Rivera, C.P., Deegan, T.D., Chen, Y., Wightman, M., Toth, R., Labib, K.P.M., Mathea, S., Ranson, N., Fernandez-Busnadiego, R., Muqit, M.M.(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, M.A., Zeng, Z.W., Toth, R., Durcan, T.M., Springer, W., Fon, E.A.*, Muqit, M.M.*, Trempe, J-F*. (2023) Structure-based design and characterization of Parkin activating mutations. Life Sci Alliance 6: e202201419
4. Antico, O., Ordureau, A., Stevens, M., Singh, F., Gierlinski, M., Barini, E., Rickwood, M.L., Prescott, A., Toth, R., Ganley, I., Harper, J.W.*, Muqit, M.M.* (2021) Global ubiquitylation analysis of mitochondria in primary neurons identifies physiological Parkin targets following activation of PINK1. Science Adv 7: (46) eabj0722
5. Singh, P., K., Muqit M. M. (2020) Parkinson’s: A Disease of Aberrant Vesicle Trafficking Annu Rev Cell Dev Biol Aug4. Doi: 10.1146/annurev-cellbio-100818-125512.