University of Dundee

Professor Miratul Muqit FRSE

Elucidation of the PINK1 signaling pathway in Parkinson’s disease
Position: 
Wellcome Trust Senior Research Fellowship in Clinical Science and Programme Leader
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 388377, int ext 88377
Email: 

Biography

Miratul graduated in Medicine with Honours from the University of Edinburgh in 1997. He was awarded a prestigious Kennedy Scholarship to study Neurobiology at Harvard University undertaking Huntington’s disease research in Mel Feany’s laboratory in 2001. He obtained his PhD in 2007 from the UCL Institute of Neurology where he made a major contribution to the discovery of PINK1 kinase mutations in Parkinson’s disease under the supervision of Nicholas Wood FMedSci and David Latchman. In parallel he received clinical training at leading London teaching hospitals including the Hammersmith Hospital and the National Hospital for Neurology and Neurosurgery at Queen Square. He specialized in Movement Disorders training under Andrew Lees FMedSci and Kailash Bhatia.

Miratul joined the MRC PPU as a Wellcome Trust Intermediate Clinical Fellow (Sponsor: Dario Alessi FRS) in 2008 to investigate how PINK1 mutations lead to neurodegeneration in Parkinson’s. He has been a Wellcome Trust Senior Clinical Fellow since 2013 and a Consultant Neurologist since 2011. Miratul has received multiple awards for his research including the Queen Square Prize in Neurology (2006), Goulstonian Lecture of the Royal College of Physicians (2018) and Francis Crick Lecture of the Royal Society (2018). He became a member of the EMBO Young Investigator Programme in 2017 and a Fellow of the Royal Society of Edinburgh in 2020.

Research

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 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 signaling 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 [1]. 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 leads 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 [2]. We were able to demonstrate the relevance of our findings to the pathogenesis of Parkinson’s through analysis of a Parkin Ser65Ala knockin mouse and the discovery of rare Parkinson’s patients harbouring mutations of the Parkin Ser65 site [3]. 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 [4]. 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 [5]. 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 [6].

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.

Publications

Selected Publications

[1] 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. Online ahead of print

 

[2] Kazlauskaite, A., Martinez-Torres, R. J., Wilkie, S., Kumar, A., Peltier, J., Gonzalez, A., Johnson, C., Zhang, J., Hope, A. G., Peggie, M., Trost, M., van Aalten, D. M., Alessi, D. R., Prescott, A. R., Knebel, A., Walden, H., Muqit, M. M. (2015) Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation EMBO Rep 16 939-954

 

[3] McWilliams, T.G., Barini, E., Pohjolan-Pirhonen, R., Brooks, S.P., Singh, F., Burel, S., Balk, K., Kumar, A., Montava-Garriga, L., Prescott, A.R., Hassoun, S.M., Mouton-Liger, F., Ball, G., Hills, R., Knebel, A., Ulusoy, A., Di Monte, D.A., Tamjar, J., Fears, K., Smith, L., Brambila, R., Eerola-Rautio, J., Tienari, P., Corti, O., Dunnett, S.B., Ganley, I.G., Suomalainen, A., Muqit, M.M. (2018) Phosphorylation of Parkin serine 65 is essential for its activation in vivo. Open Biology 8: 180108.

 

[4] Kumar, A., Tamjar, J., Waddell, A.D., Woodroof, H.I., Raimi, O.G., Shaw, A.M., Peggie, M, Muqit, M.M.,* van Aalten, D.M.* (2017) Structure of PINK1 and mechanisms of Parkinson's disease associated mutations. eLife 6: e29945 (*Joint Senior Author)

See accompanying News and Views Article: https://www.nature.com/articles/d41586-017-07691-x

 

[5] Lai, Y. C., Kondapalli, C., Lehneck, R., Procter, J. B., Dill, B. D., Woodroof, H. I., Gourlay, R., Peggie, M., Macartney, T. J., Corti, O., Corvol, J. C., Campbell, D. G., Itzen, A., Trost, M., Muqit, M. M. (2015) Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1 EMBO J 34 2840-61

 

[6] Vieweg, S., Mulholland, K., Brauning, B., Kachariya, N., Lai, Y-C., Toth, R., Sattler, M, Groll, M., Itzen, A., Muqit, M.M. (2020) PINK1-dependent phosphorylation of Serine111 within the SF3 motif of Rab GTPases impairs effector interactions and LRRK2 mediated phosphorylation at Threonine72. Biochem J 477 1651-1668

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 ouptuts 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.