A molecular switch links a Scottish mouse, a Finnish patient and Parkinson’s disease

Researchers at the Faculty of Medicine, University of Helsinki, make an unexpected and vital contribution to an international collaborative effort in Parkinson’s disease research.
Artistic impression of patient MRI from McWilliams et al., 2018

Artistic impression of patient MRI from McWilliams et al., 2018

An international team of scientists led by the University of Dundee, UK have verified that a molecular pathway that has been studied for years under laboratory conditions, is also disrupted in Parkinson’s disease patients.

Parkinson’s disease is a relentless neurodegenerative disorder for which no cure currently exists. Mutations in two genes called PINK1 and Parkin are associated with early-onset forms of Parkinson’s. These genes encode distinct enzymes that are predicted to play a pivotal role in protecting the brain against stress.

Previous work established that PINK1 works by detecting damage to the cellular ‘power grid’, and prevents further damage by activating a critical “molecular switch” in Parkin called Serine 65. This finding published in 2012 was led by the laboratory of Professor Miratul Muqit FRCP, Wellcome Trust Senior Clinical Fellow at the MRC Protein Phosphorylation & Ubiquitylation Unit at the University of Dundee, UK. Although it remains the most cited study in Open Biology, the importance of this “molecular switch” in Parkinson’s patients has remained elusive.

To further understand its importance, Muqit developed a genetically engineered mouse to study the Parkin switch in tissues, but researchers were unaware of its significance in humans. The ambitious project was spearheaded by Tom McWilliams, who recently relocated to Finland as a Tenure Track Assistant Professor and Academy Scientist at the Faculty of Medicine, University of Helsinki. Remarkably, through a collaboration involving Academy Professor Anu Suomalainen-Wartiovaara, Professor Pentti Tienari and Risto Pohjolan-Pirhonen, MD, at Molecular Neurology Programme of University of Helsinki, a Finnish patient was also identified to have a mutation in the same Serine 65 switch.

Strikingly, both the mouse and the patient lack the ability of PINK1 to activate the Parkin enzyme. Thanks to the Progressive Parkinson’s Markers Initiative study coordinated by the Michael J. Fox Foundation, a second patient in the United States was identified. This discovery confirms the central importance of the PINK1-Parkin pathway in Parkinson’s patients and will likely prove vital for therapeutic development efforts in this area.

Remarking on the discovery, McWilliams says:

“It was particularly gratifying to see that findings from discovery-based science can have such unexpected relevance in Parkinson’s patients. The Helsinki team made an outstanding contribution to this work, and thanks to their collaborative spirit and expertise, we were able to make rapid progress in this area. It will be interesting to determine the mitophagy-independent roles of this pathway in vivo.”

The research is published today as the cover article of Open Biology, an open access of the Royal Society.

The study also involved collaborations with leading groups at Cardiff University, CNRS INSERM, Paris and the German Center for Neurodegenerative Diseases in Bonn.

For more information:

Tom McWilliams, Assistant Professor and Academy Scientist, University of Helsinki
Email: thomas.mcwilliams@helsinki.fi

Reference: McWilliams TG & al. Phosphorylation of Parkin at Serine65 is essential for its activation in vivo. Open Biology 8: 180108. http://rsob.royalsocietypublishing.org/content/8/11/180108

 

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