MRC PPU Programme Leader and Consultant Neurologist Miratul Muqit has been awarded the prestigious 2018 Francis Crick Medal and Lecture. The award is in recognition of the groundbreaking research that Miratul and his laboratory have done on the Parkinson’s disease linked PINK1-Parkin pathway.
The Francis Crick Lecture is given annually in any field of biological sciences with preference given to genetics, molecular biology and neurobiology, the general areas in which Francis Crick worked, and to fundamental theoretical work, which was the hallmark of Crick’s science. Miratul is the first practicing clinician to receive the award and the second researcher from the MRC PPU after Dario Alessi, who delivered the Crick Lecture in 2006.
In 2004 Miratul was a key member of the London-based team that discovered mutations in a gene known as PINK1 in patients with Parkinson’s. Funded by a Wellcome Trust Fellowship, he joined the MRC PPU in 2008 where he has been working on understanding the mechanism by which disruption of the PINK1 gene causes Parkinson’s.
Miratul discovered that in response to agents that damage mitochondria, PINK1 becomes active and phosphorylates and activates an enzyme called Parkin that functions as a ubiquitin E3 ligase. Excitingly, Parkin is another gene in which mutations as in PINK1 cause Parkinson’s in humans.
These findings were particularly important as they directly linked two genes that are mutated in familial Parkinson’s disease. Patients with mutations in PINK1 or Parkin also display an indistinguishable phenotype of early-onset Parkinson’s disease, which is consistent with the notion that these enzymes operate in the same signalling network. Miratul next discovered that in addition to phosphorylating Parkin, PINK1 strikingly directly phosphorylates ubiquitin. Miratul then found that PINK1-phosphorylated ubiquitin acts as a powerful allosteric activator of Parkin.
Miratul has undertaken further in-depth experiments that define the mechanism by which PINK1-phosphorylated ubiquitin not only activates Parkin but in addition recruits it to damaged mitochondria triggering their removal by mitophagy.
Recently, Miratul also discovered that PINK1 regulates the phosphorylation of multiple Rab GTPases that have also been previously implicated in Parkinson’s. This has opened up an important new line of investigation and links PINK1 into multiple lines of on-going Parkinson’s and neurodegeneration research in Rab biology.
Miratul said, “I was initially stunned to learn about this award and feel immensely privileged to be following in the footsteps of so many eminent scientists who have previously been invited to give the Crick Lecture. The award is a wonderful reflection of the strength of the scientific and clinical environment here in Dundee. I am also grateful to the talented students and postdocs who have contributed to our advances and to the patients whose optimism and hope for finding a cure for Parkinson’s is a constant inspiration. I am also grateful to the Wellcome Trust, Parkinson’s UK, the Michael J Fox Foundation and J Macdonald Menzies Trust for funding our past and present work.
Dario Alessi Director of the MRC Protein Phosphorylation and Ubiquitylation Unit stated “Miratul is one of the few people working in neurodegeneration who have a fantastic knowledge and expertise of both the medical as well as basic research arenas. This year is the two hundredth anniversary of the first clinical description of the disease by James Parkinson, and there are no current treatments to slow down the progression of the disease. Miratul’s mission is to generate fundamental knowledge and technologies that could be exploited by him as well as others to develop improved strategies to better diagnose and treat Parkinson’s in the future. He has made a tremendous start to achieving these goals. The award of the Francis Crick lecture provides a prodigious boost to Miratul’s research”.
Venki Ramakrishnan, President of the Royal Society, said, “The Royal Society has a long-standing tradition of celebrating the best and brightest scientists. The winners of this year’s medals and awards have made outstanding contributions to their field and I congratulate them for their distinguished work and the advancement of science as a whole.”