Parkinson’s is the fastest-growing brain disorder and there are still no treatments available that can slow or stop the disease. Now, new research by scientists at the University of Dundee in Scotland has discovered how to activate a gene called PINK1 that is essential for protecting brain cells from stress, a finding that provides potential new strategies for developing drugs that could benefit Parkinson’s patients.
Previous research conducted at this university had revealed the protective properties of the PINK1 gene and that in patients who carry mutations in the PINK1 gene this protective effect is lost, leading to the degeneration of the cells that control movement, thus causing the symptoms of Parkinson’s.
The PINK1 gene encodes a class of enzymes known as kinases and acts as a sensor of damage to mitochondria, which are the cells’ ‘powerhouses’. PINK1 activates a protective pathway by targeting two key proteins, ubiquitin and parkin, which are responsible for clearing damage. However, it was not known how PINK1 was activated.
New strategies for the treatment of Parkinson’s disease
In research just published in the journal Science Advances, the Dundee team of scientists, in collaboration with colleagues from the UK, the Netherlands and Germany, used biological methods and artificial intelligence to uncover a model of the inner workings of how the PINK1 enzyme is activated.
The model reveals how the PINK1 switch is activated by binding to key parts of a complex machine on the surface of mitochondria, known as the Translocase of the Outer Membrane (TOM) complex. The new findings show that PINK1 uses unique elements not found in other enzymes. These form a relay switch by which PINK1 is activated to target ubiquitin and parkin and exert its protective function against Parkinson’s.
“This molecular research allows us to better understand the underlying biology of Parkinson’s disease and provides new insights into how PINK1-controlled disease might be better diagnosed and treated.”
“As a clinician treating patients with Parkinson’s, the aim of our research is to uncover fundamental mechanisms that may point to new ways of better treating the disease in the future,” said Professor Miratul Muqit, Consultant Neurologist at the Medical Research Council Protein Phosphorylation and Ubiquitination Unit (MRC-PPU), School of Life Sciences, Dundee.
“Our new findings add to a number of emerging treatment strategies targeting the PINK1 pathway, some of which are entering clinical trials for Parkinson’s patients this year. This work provides a framework for conducting future studies aimed at finding new drug-like molecules that can target PINK1 in the TOM complex.”
“This is a bold and meticulous molecular investigation that allows us to better understand the underlying biology of Parkinson’s disease, and provides new insights into how PINK1-controlled disease could be better diagnosed and treated, opening the door to further important research,” concludes Professor Dario Alessi, Director of the MRC-PPU.
