Detection of Parkinson’s disease (PD) traditionally has never been an exact science, as many diagnoses rely on the classification of various symptoms and behavioral anomalies. However, several other neurological disorders present with very similar symptomology as PD but have entirely different clinical outcomes and treatment regimens. In recent years, scientists have searched for specific DNA and protein biomarkers that would provide them with a clear indication that a patient had PD. This approach has met with some success, yet most often clinicians need to obtain cerebrospinal fluid samples from patients through invasive and uncomfortable techniques.
Now, investigators at the University of Alabama at Birmingham (UAB) have identified a brand-new type of biomarker—a phosphorylated protein that correlates with the presence and severity of PD—measured from urine exosome fractions from 79 PD patients and 79 neurologically healthy controls. The current study utilized biobanked samples obtained from the National Institute of Neurological Disorders and Stroke (NINDS) National Repository that had been tucked away in a cold freeze for more than 5 years. The UAB team dug deep into these biobanked samples to validate the biomarker as a possible guide for future clinical treatments and a monitor of the efficacy of potential new PD drugs in real time during treatment.
“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,” explained senior study author Andrew West, Ph.D., co-director of the Center for Neurodegeneration and Experimental Therapeutics, and 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.”
Validating these biomarkers can aid both preclinical trial work in the laboratory and future clinical trials of drugs to treat PD. The UAB team and others are paving the way for an inhibitor drug that prevented neuroinflammation and neurodegeneration in an animal model of the disease. The recently released data came as a follow-up study from a work published in March that looked at LRRK2, which has been shown previously to play a role in hereditary PD, and its most common mutation—called G2019S—which causes the LRRK2 kinase to add too many phosphates to itself and other proteins.
The current study—published recently in Movement Disorders in an article entitled “Ser(P)-1292 LRRK2 in Urinary Exosomes Is Elevated in Idiopathic Parkinson's Disease”—expanded the scope to people without LRRK2 mutations, which is most PD patients.
Using 158 urine samples from PD patients and healthy controls enrolled in the UAB Movement Disorder Clinic as part of the NIH Parkinson's Disease Biomarker Program, the UAB team found that approximately 20% of people without LRRK2 mutations but with PD also showed highly elevated phosphorylated LRRK2, similar to people with LRRK2 mutations and not present in healthy controls. The study speculates that people with elevated phosphorylated LRRK2 may be particularly suitable candidates for future drugs that reduce phosphorylated LRRK2.
The key to this new biomarker approach was the recognition that LRRK2 can be purified from a type of cellular vesicle called the exosome that is 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. The investigators were able to purify exosomes from 3- or 4-ounce urine samples donated by patients and then measure phosphorylated LRRK2 in those exosomes.
While the research team was excited by their preliminary findings, they are looking to explore further where the urinary exosomes come from and what role LRRK2 has in PD.