A protein previously thought to be involved in just a small percentage of Parkinson's disease cases now appears to be implicated in a much greater number, if not the whole patient population, a new study suggests.
This finding opens a novel therapeutic approach to Parkinson's disease to a much greater target patient population.
The study focused on the LRRK2 protein, which has previously been found to be overactivated by mutations in the LRRK2 gene, implicated in about 3% of Parkinson's cases.
"We previously thought that the overactivation of the LRRK2 protein was only involved in Parkinson's disease in patients carrying mutations in the LRRK2 gene," senior author J. Timothy Greenamyre, MD, professor of neurology at the University of Pittsburgh School of Medicine, Pennsylvania, told Medscape Medical News. "But our latest studies suggest that actually the LRRK2 protein is also hyperactive in the idiopathic sporadic form of the disease — so probably in the vast majority of Parkinson's disease patients."
Their findings have important implications, he added. "They suggest that therapeutic intervention targeted at LRRK2 inhibition might be applicable to most patients with Parkinson's, not just the 3% to 4% of genetic cases that we previously thought."
Several companies are now developing inhibitors of LRRK2 activation, the first of which are about to enter clinical trials.
"Our paper suggests that the scope for these drugs is much larger than previously believed. What was developed initially for just a very small subset of Parkinson's patients now looks to be relevant to the whole Parkinson's population," Greenamyre said.
The study was published online in Science Translational Medicine on July 25.
Using a new fluorescent sensor for LRRK2 activity, the researchers examined postmortem brain tissue from patients with Parkinson's disease who did not have mutations in the LRRK gene. They found that compared with 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.
The researchers also found that activity in LRRK2 was increased in rat models of Parkinson's disease and was also associated with the accumulation of α-synuclein, a process that leads to the formation of Lewy bodies in the brain, a hallmark of the disease. And when the animals were treated with a drug that blocks LRRK2 activity, the accumulations of α-synuclein and Lewy body formation were both prevented.
In addition, reactive oxygen species (ROS), which were increased in the brains of the rat models of Parkinson's, were linked to increased activity of LRRK2, and when the production of reactive oxygen species was blocked, LRRK2 activation was not seen.
"The results presented here suggest that wild-type LRRK2 is activated by ROS in dopamine neurons in iPD [idiopathic Parkinson's disease] and that this, in turn, may trigger a downstream pathological cascade of events culminating in neurodegeneration," the researchers write.
"We found that LRRK2 was activated by oxidative stress, and if we prevent overactivation of LRRK2 we could prevent much of the pathology of Parkinson's disease," Greenamyre added.
The researchers next plan to study whether the neurodegeneration that results from LRRK2 overactivity can be prevented and to identify the mechanisms that connect environmental stressors to LRRK2 activation.
Greenamyre explained that LRRK2 is involved in phosphorylating a variety of proteins. "We believe that in Parkinson's disease the overactivation of LRRK2 leads to increased phosphorylation of α-synuclein and increased lysosomal dysfunction."
He believes LRRK2 will now become a key target central to the prevention of Parkinson's progression.
"This is a very exciting time for Parkinson's disease therapeutics," he added. "It's the first time there have been disease-modifying therapies on the horizon."
Several other approaches are also in development, including targeting α-synuclein itself and glucagon-like protein-1, he added. "I think these different targets are probably involved in the pathology of Parkinson's at different points, but targeting all of them may have an additive effect."
Commenting for Medscape Medical News, Beth-Anne Sieber, PhD, program director at the National Institute of Neurological Disorders and Stroke, which supported the research, said the paper adds another piece to the puzzle that is Parkinson's disease.
"These striking findings suggest that LRRK-2 plays a major role in Parkinson's etiology and thus becomes an exciting target for the development of new potential therapeutics," she said.
She noted that the first LRRK-2 inhibitors hit problems with lung toxicity but newer compounds are now in development — and this research should stimulate renewed interest in this field.
This study was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Institute of Environmental Health Services, the Blechman Foundation, the American Parkinson Disease Association, University of Pittsburgh Brain Institute, Michael J. Fox Foundation, Medical Research Council, and friends and family of Sean Logan.
Sci Transl Med. Published online July 25, 2018. Abstract
https://www.medscape.com/viewarticle/900451
No comments:
Post a Comment