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Protein Affected By Rare Parkinson's Mutation May Lurk Behind Many Cases

July 30, 2018

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Neurology
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Parkinson's disease (PD) is a neurodegenerative disorder that affects predominately dopamine-producing ("dopaminergic") neurons in a specific area of the brain called substantia nigra. Symptoms generally develop slowly over years. The progression of symptoms is often a bit different from one person to another due to the diversity of the disease. People with PD may experience: tremor (mainly at rest and described as pill rolling tremor in hands), bradykinesia (slowness of movement), limb rigidity, and gait/balance problems.

Mutations in the gene LRRK2 have been linked to about 3% of PD cases. Now, according to an article published in Science Translational Medicine (25 July 2018), evidence has been found that the activity of LRRK2 protein might be affected in many more patients with PD, even when the LRRK2 gene itself is not mutated. More than 10 years ago, researchers linked mutations in the LRRK2 gene with an increased risk for developing PD. The observed mutations produce a version of LRRK2 protein that behaves abnormally and is much more active than it would be normally. Despite its importance in PD, the very small amount of normal LRRK2 protein in nerve cells made it difficult to study. In the current study, the authors developed a new method for observing LRRK2 cells that made them glow fluorescently only when LRRK2 was in its activated state. The authors also used detection of fluorescent signals to demonstrate loss of binding of an inhibitor protein to LRRK2 when LRRK2 was activated.

For the study, the authors looked first at postmortem brain tissue from PD 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 PD. This suggested that increased LRRK2 activity could be a common feature of the disease. To get a closer look at how LRRK2 activity is related to Parkinson's disease. The authors next turned to rodent models of the disorder. The sensitivity of their new technique allowed for the direct study of LRRK2 activity, which until now could not be done. By injecting rodents with the environmental toxin rotenone and studying the effect on LRRK2, the authors 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 of the disease, 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 PD. The authors also observed that reactive oxygen species (ROS), compounds that can interact and affect other components within cells, 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.

According to the authors, the findings suggest that both genetic and environmental causes of PD can be tied back to the activity of LRRK2 protein. The authors added that 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.

More Information: 

PD Information Page

Patient and Caregiver Information

NINDS NIH

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