A recent research has indicated that a protein initially believed to affect a little proportion of Parkinson’s disease cases now looks caught up in a larger, if not whole, proportion of the patients. A much higher Parkinson’s disease target group has now been opened to an innovative therapeutic method. An LRRK2 protein, involved in approximately three percent of cases, initially over-activated by mutations in LRRK2 gene, was the focus of the research.
This latest study has revealed that the LRRK2 protein was not only involved in over-activation of the protein in Parkinson’s disease patients carrying the LRRK2 gene, but it is also hyperactive in, probably, great population of Parkinson’s disease patients, as shown in idiopathic sporadic type of the disease. This study that was published onlinehas some critical implications. The therapeutic intervention aimed at LRRK2 inhibition might not only affect the 3 to 4 percent genetic cases previously known, but it might affect almost all cases of Parkinson’s disease patients.
Consequently, many pharmaceutical companies are at the moment developing LRRK2 activation inhibitors, the initial groups are not far off from entering clinical trials. The research suggests that the range of the drugs is far bigger than earlier understood. It now seems that what was produced was for a small minority of patients is now set to be applicable to the entire population of Parkinson’s disease. The research was published onlinein Science Transitional Medicine, 25thJuly, 2018.
Postmortem brain tissue of Parkinson’s disease patients having no mutations in the LRRK2 gene was examined by the researchers, using a new fluorescent sensor for LRRK2 action. They discovered that there was a remarkable boost in the activity of LRRK2 in the dopamine containing neurons of substantia nigra, the region implicated mostly in Parkinson’s patients.
In addition, the researchers also discovered that there was a boost in activity of LRRK2, with associated accumulation ofα-synuclein, in Parkinson’s disease of rat models. A situation that produced the development of Lewy bodies in the brain, a classic feature of the disease. Also accumulation ofα-synuclein and Lewy bodies were hindered when animals were treated with LRRK2 blockers/ inhibitors. Furthermore, LRRK2 activation was unnoticed when the creation of reactive oxygen species, which were elevated in the brains of Parkinson’s rat models, was inhibited, and were also linked to LRRK2 increased activity.
Based on the findings of the researchers, the results suggest that ROS in dopamine neurons in idiopathic Parkinson’s disease (iPD) was activated by a wild-type LRRK2, which, consecutively, may initiate a downstream pathological flow of actions leading to neurodegeneration. It was also found that majority of pathology of Parkinson’s disease could be prevented if over-activation of LRRK2 is inhibited, since LRRK2 was noted to be activated by oxidative stress, according to the researchers.
Besides, the researchers decided to detect the mechanisms that linked LRRK2 activation to environmental stressors, and to find out whether the LRRK2 over-activity that leads to neurodegeneration can be prevented. Since LRRK2 is involved in different kind of protein phosphorylation, the researchers opined that over-activation of LRRK2 produced increased lysosomal dysfunction and higher phosphorylation in Parkinson’s. Hence, LRRK2 should become the main target fundamental to the inhibition of Parkinson’s advancement. It is great time in therapeutics of Parkinson’s disease: the horizon is bright with disease-modifying therapies.
Moreover, several approaches to management of Parkinson’s are in development, including targeting glucagon-1 and α-synuclein itself, but they seem to be involved in other points of Parkinson’s disease pathology: targeting everyone of them may create additive consequence.
In conclusion, these remarkable findings imply that LRRK-2 plays a main function in etiology of Parkinson’s and it has become a stimulating target for novel prospective therapeutics.
This research was supported by the National Institute on Aging, The Blechman Foundation, The National Institute of Environmental Health Services, the National Institute of Neurological Disorders and Stroke, the American Parkinson’s Disease Asociation, Micheal J.Fox Foundation, University of Pittsburg Brain Institute, Friends and Family of Sean Logan and Medical Research Council.
Author: Dr Omotayo Omojola