Researchers from the University of Alabama at Birmingham have found that a new urinary biomarker, SER(P)-1292 LRRK2, correlates with Parkinson’s disease. Early studies indicate that this phosphorylated LRRK2 protein could potentially be used as a diagnostic/prognostic marker or a therapeutic target to treat patients with Parkinson’s disease. These preliminary findings were recently published in two separate journals, Neurology and Movement Disorders, in March and June 2016, respectively.
Parkinson’s Disease is a progressive, neurodegenerative chronic disorder. While the causes of Parkinson’s disease remain largely unknown, genetic mutations in the leucine-rich repeat kinase 2 (LRRK-2) gene have been shown to play a role in hereditary Parkinson’s Disease. The most common mutation, G2019S, increases autophosphorylation of LRRK2 protein especially at the Ser-1292 residue located near the GTPase domain of the protein. With support from the Michael J. Fox foundation for Parkinson’s disease, the National Institutes of Health (NIH) and the Parkinson’s Disease Foundation, Dr. West and his team isolated exosomes from biobanked urine samples donated by patients with Parkinson’s Disease to measure levels of SER(P)-1292 LRRK2 in these exosomes.
So can urinary LRRK2 phosphorylation predict Parkinson’s Disease?
In the Neurology study, the research team observed that elevated levels of Ser(P)-1292 LRRK2 was a predictor of Parkinson’s Disease amongst patients with the LRRK2 G2019S mutation. This was examined under blinded conditions in urine samples collected from two separate all-male patient cohorts. Participants consisted of patients with and without the mutation with and without clinical presentation of Parkinson’s Disease.
A subsequent study published in Movement Disorders measured levels of the LRRK2 phosphorylated protein (Ser(P)-1292 LRRK2) in a large cohort of Parkinson’s Disease patients, however, this time with no LRRK2 mutations. Analysis of the 158 urine samples collected from both male and female Parkinson Disease sufferers and healthy controls revealed that gender had an effect on phosphorylated LRRK2 levels with higher levels observed in male participants. When adjusted for this effect, the levels of phosphorylated LRRK2 were elevated in the entire Parkinson’s Disease cohort when compared to the control. More importantly, higher levels of phosphorylated LRRK2 were observed in Parkinson’s disease patients with poor performance in clinical assessments.
Phosphorylated LRRK2 – a promising marker that requires further investigation.
More research is required to determine the source of the urinary phosphorylated LRRK2. There are currently no diagnostic tests for Parkinson’s disease and diagnosis is primarily based on visual clinical assessment. The treatment options available only alleviate symptoms caused by the disease. This discovery may provide a novel biomarker and therapeutic target for Parkinson’s Disease sufferers. The research group has recently published a study in the Journal of Neuroscience evaluating LRRK2 kinase inhibitors which prevents alpha-synuclein inclusion formation in neurons, a key feature in Parkinson’s Disease. Indeed phosphorylated LRRK2 could be used as a prognostic marker to assess the efficacy of these inhibitors.