Last updated July 26, 2018 at 9:28 am
Study suggests even the ‘normal’ version may be implicated.
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A gene linked to Parkinson’s disease may be having a greater impact than first thought.
A decade ago mutations in the gene LRRK2 were linked to about three per cent of Parkinson’s cases, but new US research has shown how normal LRRK2 may contribute to the development of the disease and has identified the gene as an integral protein in the neurobiological pathways affected by the disease.
It’s been a tricky area to work in because there is so little normal LRRK2 protein in nerve cells.
In their recent study, the researchers developed a way to make LRRK2 cells glow fluorescently when in an activated state. They also used detection of fluorescent signals to demonstrate loss of binding of an inhibitor protein to LRRK2 when LRRK2 is activated.
A fluorescent sensor reveals LRRK2 activity. Courtesy Greenamyre Lab.
They looked first at post-mortem brain tissue from Parkinson’s disease patients who did not have mutations in LRRK2. Compared to healthy individuals of similar ages, there was a striking increase in LRRK2 activity in the dopamine-containing neurons of the substantia nigra, the area of the brain most affected in Parkinson’s disease. This suggested that increased LRRK2 activity could be a common feature of the disease.
“This finding provided strong evidence that something is causing LRRK2 activity to increase in Parkinson’s disease patients, specifically in the area of the brain we would expect based on what we know of the disease,” said senior author J. Timothy Greenamyre, director of the Pittsburgh Institute for Neurodegenerative Diseases.
The researchers next turned to rodent models of the disorder, the sensitivity of their new technique allowing for direct study of LRRK2 activity for the first time.
By injecting rodents with the environmental toxin rotenone and studying the effect on LRRK2, they linked increased LRRK2 activity with the accumulation of alpha-synuclein, a process that leads to the formation of Lewy bodies in the brain, a hallmark of Parkinson’s disease.
In another model, where synuclein was present in much higher amounts than normal, LRRK2 activity was increased. In contrast, when the animals were treated with a drug that blocks LRRK2 activity, the accumulation of alpha-synuclein and Lewy body formation were both prevented.
Finally, additional links were found between LRRK2 activity and the potentially damaging consequences of Parkinson’s disease. Reactive oxygen species (ROS) are compounds that can interact and affect other components within cells, and ROS were increased in the brains of both rodent models. ROS were seen to increase the activity of LRRK2, and when ROS production was blocked, LRRK2 activation was not observed.
“Our findings suggest that both genetic and environmental causes of Parkinson’s disease can be tied back to the activity of LRRK2 protein,” Greenamyre said. “This is important, because it suggests that the drugs being developed for patients with the LRRK2 mutation, which represent a very small percentage of the affected population, could benefit a much greater number of people with the disease.”
The paper published in Science Translational Medicine.
