Andrew West. Credit: UAB
Stored samples of urine and CSF from patients with Parkinson’s disease hold a brand-new type of biomarker – a phosphorylated protein that correlates with the presence and severity of Parkinson’s disease. “Nobody thought we’d be able to measure the activity of this huge protein called LRRK2 in biofluids since it is usually found inside neurons in the brain,” said Prof. West. “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.”
LRRK2, has been shown to play a role in hereditary Parkinson’s, and the most common of these mutations – G2019S – causes the LRRK2 kinase to add too many phosphates to itself and other proteins. Why this leads to Parkinson’s disease is not yet clear.
The key to West’s biomarker approach 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.
They found elevated phosphorylated LRRK2 predicted the risk for onset of Parkinson’s disease for people carrying a mutation in LRRK2, which is about 2-3% 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 to ensure the approach was rigorous.
The follow-up Movement Disorders paper – the first study of its type – expanded the scope to people without LRRK2 mutations, which is most Parkinson’s disease patients. 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 ~20% 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.
Questions remain for this evidence of biochemical changes in LRRK2 in idiopathic Parkinson’s disease. One is finding out where the urinary exosomes come from. Given a suspected role for inflammation in Parkinson’s disease, it is interesting that LRRK2 is highly expressed in cells of the innate immune system. A possible explanation for the phosphorylated LRRK2 in patients with more severe disease may be an increased inflammation in those patients who have aggressive progression of disease.
In May, West was awarded a new U01 collaborative grant from the National Institute of Neurological Disorders and Stroke to further explore urinary exosomes and extend the observations to cerebral-spinal fluid as a marker for disease prediction and prognosis. http://www.uab.edu/news/innovation/item/7419-parkinson-s-disease-biomarker-found-in-patient-urine-samples
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