It is generally recognized that there are inadequate measures of detecting disease progression and biochemical pathways associated with Parkinson's disease (PD) in clinical populations, and that this lack of effective biomarkers has hindered, and is expected to continue to impede, successful clinical trials for efficacious neuroprotective (disease-retarding or halting) therapeutics. Genetic and pathological studies have identified several proteins linked to late-onset PD, and these proteins have provided insight into pathways that might be central to disease. However, these proteins have been difficult to analyze in PD cases due to the limited availability of disease-susceptible tissue, and studies are usually confined to post-mortem derived specimens. We have made the recent observation that LRRK2, and other proteins linked genetically and pathologically to PD, are detectable in exosomes isolated from human urine samples. Using a multiplex mass spectrometry approach, we can quantify 935 proteins from clinical urine exosome samples, and 140 of these proteins are linked to neurodegeneration by pathway analysis. This proposal seeks to 1) determine whether there are biomarkers associated with PD susceptibility and/or progression in urinary exosome-proteomes derived from PD patients versus controls, and 2) to determine if LRRK2 expression and/or phosphorylation are significantly lowered in the urinary exosomes of individuals treated with the potent LRRK2 kinase inhibitor sunitinib (a multi-kinase inhibitor compound), to establish an assay for on-target effects for future LRRK2 inhibitor clinica trials. Potential biomarkers of interest will be validated in replication cohorts, and the most promising leads will be further explored in future multi-center studies.
Over one-million Americans may be affected with Parkinson's disease, a devastating neurodegenerative disorder for which there is no cure. This proposal will seek out new markers to aid in disease diagnosis and tracking of disease progression, which may directly benefit patients affected with Parkinson's disease and help power future clinical trials for the discovery of new therapeutics.
|West, Andrew B (2015) Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic. Mov Disord 30:180-9|
|West, Andrew B; Cowell, Rita M; Daher, João P L et al. (2014) Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol 522:2465-80|
|Fraser, Kyle B; Moehle, Mark S; Daher, Joao P L et al. (2013) LRRK2 secretion in exosomes is regulated by 14-3-3. Hum Mol Genet 22:4988-5000|