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 nearly 20 genes that are mutated in familial forms of the 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. 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 lead to Parkinson’s. Multiple lines of evidence 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.

We have discovered the key downstream substrates of PINK1 including the RBR E3 ligase, Parkin, and ubiquitin and elucidated the mechanism of activation of Parkin E3 ligase activity by phosphorylated-ubiquitin. To date PINK1 is the only known ubiquitin kinase and we have a major interest in understanding this interplay between phosphorylation and ubiquitin to signaling mechanisms. More recently we have uncovered a new PINK1-dependent regulation of Rab GTPases whose functional link to Parkinson’s disease remains to be solved.

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


Odetta Antico | PhD Student
Christa Baker | PhD Rotation Student
Poonam Kadade | Postdoctoral Researcher
Fiachra McEnaney | PhD Rotation Student
Katie Mulholland | PhD Student
Pawan Singh | Postdoctoral Researcher
Daniel Saarela | Visiting Undergraduate
Andrew Shaw | PhD Student
Michael Stevens | Postdoctoral Researcher
Ilaria Volpi | Postdoctoral Researcher
Andrew Waddell | PhD Student
Michael Whitehead | Postdoctoral Researcher

Selected Publications

McWilliams, T.W., Muqit, M.M. (2017) PINK1 and Parkin: emerging themes in mitochondrial homeostasis Curr Opin Cell Biol 45 83-91
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
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
Kazlauskaite, A., Kondapalli, C., Gourlay, R., Campbell, D. G., Ritorto, M. S., Hofmann, K., Alessi, D. R., Knebel, A., Trost, M., Muqit, M. M. (2014) Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65 Biochem J 460 127-139
Kazlauskaite, A., Kelly, V., Johnson, C., Baillie, C., Hastie, C. J., Peggie, M., Macartney, T., Woodroof, H. I., Alessi, D. R., Pedrioli, P. G., Muqit, M. M. (2014) Phosphorylation of Parkin at Serine65 is essential for activation: elaboration of a Miro1 substrate-based assay of Parkin E3 ligase activity Open Biol 4 130213
Kondapalli, C., Kazlauskaite, A., Zhang, N., Woodroof, H. I., Campbell, D. G., Gourlay, R., Burchell, L., Walden, H., Macartney, T. J., Deak, M., Knebel, A., Alessi, D. R., Muqit, M. M. (2012) PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 Open Biol 2 120080