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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Demonstration--Cooperative Agreements (U18)
Project #
1U18NS082132-01
Application #
8472329
Study Section
Special Emphasis Panel (ZNS1-SRB-J (02))
Program Officer
Babcock, Debra J
Project Start
2012-09-30
Project End
2015-12-31
Budget Start
2012-09-30
Budget End
2013-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$293,000
Indirect Cost
$93,000
Name
University of Alabama Birmingham
Department
Neurology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Fraser, Kyle B; Moehle, Mark S; Alcalay, Roy N et al. (2016) Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers. Neurology 86:994-9
Fraser, Kyle B; Rawlins, Ashlee B; Clark, Rachel G et al. (2016) Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson's disease. Mov Disord 31:1543-1550
Rosenthal, Liana S; Drake, Daniel; Alcalay, Roy N et al. (2016) The NINDS Parkinson's disease biomarkers program. Mov Disord 31:915-23
West, Andrew B; Cookson, Mark R (2016) Identification of bona-fide LRRK2 kinase substrates. Mov Disord 31:1140-1
Boddu, Ravindra; Hull, Travis D; Bolisetty, Subhashini et al. (2015) Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury. Hum Mol Genet 24:4078-93
West, Andrew B (2015) Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic. Mov Disord 30:180-9
Olanow, C Warren; Kieburtz, Karl; Odin, Per et al. (2014) Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol 13:141-9
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, João P L et al. (2013) LRRK2 secretion in exosomes is regulated by 14-3-3. Hum Mol Genet 22:4988-5000