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University of Alabama researchers find Parkinsonís disease biomarker in urine samples
As University of Alabama at Birmingham (UAB) media relations writer Jeff Hansen noted recently of recent UAB research, “For more than five years, urine and cerebral-spinal fluid samples from patients with Parkinson’s disease have been locked in freezers in the NINDS National Repository, stored with the expectation they might someday help unravel the still-hidden course of this slow-acting neurodegenerative disease.”
Well, out of the freezer and potentially into the fire of therapeutic R&D and more personalized medicine, apparently.
According to UAB, research by Dr. Andrew West and colleagues at the university indicates that, more than simply urine, those biobanked urine samples hold “a brand-new type of biomarker—a phosphorylated protein that correlates with the presence and severity of Parkinson’s disease.”
West and his team are now doing further research with regard to these sample to validate the biomarker. If it proves effective as a marker, it could possibly be used to monitor of the efficacy of potential new Parkinson’s drugs in real time—both at the preclinical and clinical trials levels—and, for clinical care, serve to guide treatment decisions for patients for more precise medical care.
In this effort, West and his colleagues have garnered support from the National Institutes of Health, the Michael J. Fox Foundation for Parkinson’s Disease Research and the Parkinson’s Disease Foundation.
“Nobody thought we’d be able to measure the activity of this huge protein called LRRK2 (pronounced lark two) in biofluids, since it is usually found inside neurons in the brain,” said West, co-director of the Center for Neurodegeneration and Experimental Therapeutics and the John A. and Ruth R. Jurenko Professor of Neurology at UAB. “New biochemical markers like the one we’ve discovered together with new neuroimaging approaches are going to be the key to successfully stopping Parkinson’s disease in its tracks. I think the days of blindly testing new therapies for complex diseases like Parkinson’s without having active feedback both for ‘on-target’ drug effects and for effectiveness in patients are thankfully coming to an end.”
The new biomarker findings were published in Neurology in March and Movement Disorders in June. The biomarker, LRRK2, has been shown to play a role in hereditary Parkinson’s, and the most common of these mutations—called G2019S—causes the LRRK2 kinase to add too many phosphates to itself and other proteins. More research is needed, however, as to why this might lead to Parkinson’s disease, UAB notes.
The key to West’s biomarker approach, UAB explains, “was the recognition that LRRK2 can be purified from a new type of vesicle called exosomes found in all human biofluids, like urine and saliva. Cells in the body continually release exosomes that contain a mixture of proteins, RNA and DNA derived from different kinds of cells. West and colleagues were able to purify exosomes from 3- or 4-ounce urine samples donated by patients, and then measure phosphorylated LRRK2 in those exosomes.”
In the Neurology study, the team found that elevated phosphorylated LRRK2 predicted the risk for onset of Parkinson’s disease for people carrying a mutation in LRRK2, which is between 2 and 3 percent of all Parkinson’s disease patients. These findings were first tested with a preliminary, 14-person cohort of urine samples from the Columbia University Movement Disorders Center. That was followed by a larger replication study of 72 biobanked urine samples from the Michael J. Fox Foundation LRRK2 Cohort Consortium. All samples were provided to UAB in a blinded fashion.
The follow-up Movement Disorders paper expanded the scope to people without LRRK2 mutations. Using 158 urine samples from Parkinson’s disease patients and healthy controls enrolled in the UAB Movement Disorder Clinic as part of the NIH Parkinson’s Disease Biomarker Program, West and colleagues found that approximately 20 percent of people without LRRK2 mutations but with Parkinson’s disease also showed highly elevated phosphorylated LRRK2 similar to people with LRRK2 mutations, and this was not present in healthy controls. The study speculates that people with elevated phosphorylated LRRK2 may be particularly good candidates for future drugs that reduce phosphorylated LRRK2.