?Exosome LRRK2 in Predicting Parkinson Disease Phenotypes? There is a critical need for quantitative biomarkers that predict Parkinson disease (PD) susceptibility and progression. Such biomarkers would aid the development of new therapies that slow or halt disease. PD has a clear genetic component that contributes to disease susceptibility. One gene in particular, leucine-rich repeat kinase 2 (LRRK2), harbors pathogenic missense mutations prevalent in some populations. LRRK2 is further linked to PD susceptibility through genome-wide association studies. Pathogenic LRRK2 mutations upregulate LRRK2 kinase activity and increase levels of the autophosphorylated residue serine S1292 (pS1292). In our previous project ?Exploratory Laboratory and Analysis Projects in PDBP? (U18 NS082132), we focused our efforts on analyzing and measuring LRRK2 in clinical samples. We discovered that autophosphorylated LRRK2 (pS1292-LRRK2) could be detected and quantified in exosome fractions from both cerebral-spinal fluid (CSF) and urine. We found elevated levels (~5 fold) of pS1292-LRRK2 in urinary exosomes from G2019S-LRRK2 mutation carriers with PD. In G2019S-LRRK2 mutation carriers, pS1292-LRRK2 levels successfully predicting clinical PD manifestation. We further analyzed pS1292-LRRK2 in a large cohort of cases and controls (n=160) from the University of Alabama at Birmingham Parkinson?s Disease Biomarker Program (UAB PDBP) and found that pS1292-LRRK2 levels predicted PD phenotypes in patients. Here we will determine the potential of exosome pS1292-LRRK2, purified from urine and CSF, in predicting PD susceptibility and progression in both early and mid-stage idiopathic PD cases as well as in LRRK2 mutation carriers. Project success will include the discovery of novel insights into the role of LRRK2 in the pathogenesis of PD and the development of a novel biomarker (exosome pS1292-LRRK2) that may predict PD manifestation in LRRK2 mutation carriers. The successful prediction of LRRK2 mutation carriers that will go on to develop PD would aid in future clinical trial design for LRRK2-directed therapies. Finally, we predict that the novel biomarker exosome pS1292- LRRK2 may help stratify idiopathic PD patients that will experience rapid progression of PD symptoms from those with more benign disease courses. Identification of PD cases with a poor prognosis would assist physicians in making treatment choices and clinical trial design for novel neuroprotective therapies.

Public Health Relevance

?Exosome LRRK2 in Predicting Parkinson Disease Phenotypes? Parkinson disease (PD) is the second most common neurodegenerative disorder. There are a lack of biochemical markers of disease prediction and progression. Our project will explore a particular form of a protein linked to PD called LRRK2 in biofluids collected over several years to determine the suitability as a new marker for disease prediction and prognosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01NS097028-02S1
Application #
9617038
Study Section
Program Officer
Sutherland, Margaret L
Project Start
2018-03-01
Project End
2019-05-31
Budget Start
2018-03-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Wang, Shijie; Liu, Zhiyong; Ye, Tao et al. (2017) Elevated LRRK2 autophosphorylation in brain-derived and peripheral exosomes in LRRK2 mutation carriers. Acta Neuropathol Commun 5:86
Abdelmotilib, Hisham; West, Andrew B (2017) Breathing new life into an old target: pulmonary disease drugs for Parkinson's disease therapy. Genome Med 9:88
Gwinn, Katrina; David, Karen K; Swanson-Fischer, Christine et al. (2017) Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program. Biomark Med 11:451-473
West, Andrew B (2017) Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp Neurol 298:236-245
West, Andrew B; Cookson, Mark R (2016) Identification of bona-fide LRRK2 kinase substrates. Mov Disord 31:1140-1