University of Dundee scientists have discovered a new target that could herald the development of new drugs to treat Parkinson’s disease.
Experts from the University’s MRC Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU) and School of Medicine have identified a means of manipulating a major cause of the currently incurable condition, building on breakthrough knowledge originally made at Dundee.
The research was funded by the Michael J. Fox Foundation, Medical Research Council, Wellcome Trust and EMBO.
More than two decades ago, MRC-PPU research revealed mutations in two genes - PINK1 and Parkin - as a major cause of early-onset Parkinson’s. Brain cells are highly dependent on energy produced from battery-like structures known as mitochondria, however, damage to these and their subsequent accumulation is linked to a slew of brain disorders, including Parkinson’s. PINK1 and Parkin acts as molecular switches to signal the removal of damaged mitochondria and thereby prevent brain cell loss, but to date it has been challenging to develop drugs that directly switch these genes on.
However, in new research published in the journal Science Advances, the Dundee team found that silencing one gene in an entirely different pathway, encoding an enzyme known as HRI or EIF2AK1, dramatically elevated pathway activation.
HRI plays a role in cell stress response pathways but had not previously been implicated in Parkinson’s. Inhibitors of cell stress response have previously been developed and the team showed that one inhibitor called ISRIB was able to block HRI and boost PINK1 and Parkin’s ability to remove damaged mitochondria.
Professor Miratul Muqit, a Consultant Neurologist at the MRC-PPU, said, “The build-up of damaged mitochondria in the brain has emerged as a major mechanism for why brain cells are lost in Parkinson’s, with clinical trials underway targeting the PINK1 pathway.
“However, our discovery that HRI acts as a molecular brake in the PINK1 pathway opens up completely unanticipated ways to develop new medicines that can reduce the accumulation of damaged mitochondria as a treatment for Parkinson’s and related brain disorders.
“Of clinical relevance, there are already drugs available like ISRIB which have proven to be safe in humans, and our findings indicate that these could be repurposed for testing in clinical trials of Parkinson’s patients right away.”
Since joining the University in 2008, Professor Muqit’s laboratory has been responsible for revealing the secrets of how mutations in the PINK1 gene lead to the build-up of damaged mitochondria in brain cells. This work has led to the development of new biomarkers for diagnosing Parkinson’s and new strategies to treat the disease that are being explored by biotechnology and pharmaceutical companies. This new research is just the latest success for Professor Muqit and his team, following on from an announcement earlier this year that will see him lead a new project aimed at accelerating the rate at which scientific discoveries in Parkinson’s disease reach patients.
Professor Dario Alessi, Director of the MRC-PPU, said, “This exciting discovery exemplifies the importance of fundamental collaborative research involving numerous groups in our unit and Schools of Life Sciences and Medicine, to reveal entirely new drug targets for diseases like Parkinson’s. By identifying HRI as a critical brake on the PINK1-Parkin pathway, the team has uncovered a promising therapeutic angle that could accelerate the development of treatments aimed at preserving brain cell health. It’s especially encouraging that compounds targeting this pathway already exist, potentially allowing for much faster translation into clinical benefit for patients.”
The research team included Dr Ian Ganley and Dr Adrien Rousseau from the MRC-PPU and Dr Glenn Masson from the School of Medicine at the University of Dundee.