Miratul Muqit's Research Group

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PINK1 kinase signalling networks in Parkinson's disease

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.

 

PINK1 kinase signalling networks in Parkinson's disease
PINK1 kinase signalling networks in Parkinson's disease

 

Clockwise from back left: Fiachra McEnaney, Odetta Antico, Pawan Singh, Michael Stevens, Ilaria Volpi, Poonam Kadade, Miratul Muqit, Andrew Waddell, and Olivia Lambourne
Clockwise from back left: Fiachra McEnaney, Odetta Antico, Pawan Singh, Michael Stevens, Ilaria Volpi, Poonam Kadade, Miratul Muqit, Andrew Waddell, and Olivia Lambourne

People

Odetta Antico | PhD Student
Christa Baker | PhD Rotation Student
Poonam Kadade | Postdoctoral Researcher
Pawan Singh | Postdoctoral Researcher
Olawale Raimi | Postdoctoral Researcher
Michael Stevens | Postdoctoral Researcher
Ilaria Volpi | Postdoctoral Researcher
Andrew Waddell | PhD Student
Kevin Wu | Postdoctoral Researcher

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   Atul Kumar, Jevgenia Tamjar, Andrew D Waddell, Helen I Woodroof, Olawale G Raimi, Andrew M Shaw, Mark Peggie, Miratul MK Muqit, Daan MF van Aalten (2017) Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations Elife. 6 pii: e29985
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, Kacharia N, Lai YC, Toth R, Singh PK, Volpi I, Sattler M, Groll M, Itzen A, Muqit MMK (2020) PINK1-dependent phosphorylation of Serine111 within the SF3 motif of Rab GTPases impairs effector interactions and LRRK2 mediated phosphorylation at Threonine72 Biochem J pii: BCJ20190664. doi: 10.1042/BCJ2019066