University of Dundee

Dundee-Harvard collaboration reveals blueprint of Parkinson’s targets

12 Nov 2021

Scientists at the University of Dundee and Harvard Medical School have identified the key targets of an enzyme that play a critical role in protecting the brain against the development of Parkinson’s disease.

Parkinson’s disease is the fastest growing degenerative disorder of the brain. Patients develop involuntary movements and increasing disability. To date there is no cure or treatments that can slow the disease course.

Mutations in the Parkin gene are a major cause of early-onset forms of Parkinson’s. Parkin encodes a specialised enzyme that is active when the energy-producing factories of brain cells, known as mitochondria, are damaged. Previous research had found that Parkin is switched on by another Parkinson’s gene, PINK1, to clear damaged mitochondria from cells and prevent brain cell loss. However, the key targets of Parkin in brain cells were unknown.

In new research, published in the journal Science Advances, two teams of scientists based in Dundee and Harvard used state-of-the-art protein sequencing technology to screen thousands of proteins in brain cells. They discovered that the active Parkin enzyme targets a common group of 22 proteins in the mitochondria of brain cells.

Their results suggest that these proteins are likely to play a critical role in protecting brain cells and ultimately patients from developing Parkinson’s disease. The teams were jointly led by Professor Miratul Muqit at Dundee and Professor Wade Harper at Harvard Medical School.

Professor Muqit, Wellcome Trust Senior Fellow and Consultant Neurologist at the University’s MRC Protein Phosphorylation and Ubiquitylation Unit, said, “We have known for several years that the Parkin enzyme operates as a switch in the brain to protect against Parkinson’s. However, until now, the targets of Parkin in brain cells have been challenging to identify.

“Combining forces with the Harper team allowed us to use state-of-the-art technologies to sift through thousands of proteins to pinpoint those controlled directly by Parkin when brain cells are stressed. The discovery paves the way for developing improved diagnostic tests for Parkinson’s patients as well as helping companies develop drugs against Parkinson’s.”

Professor Harper, Vallee Professor of Molecular Pathology and Chair of Cell Biology at Harvard Medical School, added, “Our results provide a biochemical landscape of Parkin’s action on the surface of mitochondria, and provides both a rich set of Parkin targets for biological follow-up studies while also suggesting candidate proteins for biomarkers of mitochondrial damage within neuronal cells.”

The research was funded by the Wellcome Trust, National Institutes of Health, Rosetrees Trust, Michael J Fox Foundation, Ned Goodnow, Medical Research Council, Aligning Science Across Parkinson’s (ASAP) initiative, EMBO and the Dundee Research Interest Group (DRIG).

The study involved collaboration with Dr Ian Ganley at the University of Dundee.

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