Parkinson disease (PD), one of the most devastating neurodegenerative disorders, afflicts more than one million patients in North America alone and poses an increasing economic burden on society. There is an urgent need for reliable, accurate, and inexpensive biomarkers that can aid clinicians in differential diagnosis, especially during early stages of the disease, or monitoring the disease progression. Studies using neuroimaging and cerebrospinal fluid (CSF) proteins have shown promise, but the performances of these potential markers are not optimized and their clinical utilities are limited. MicroRNAs (miRNAs), a recently discovered class of small, non- coding RNAs that regulate protein levels post-transcriptionally, play important regulatory roles in many cellular processes. Aberrant miRNA expression has become an emerging theme for a wide variety of diseases including PD and other neurodegenerative disorders. Recent studies have also reported significant levels of stable miRNAs in blood, CSF and other body fluids, raising the possibility that these miRNAs could serve as clinically useful, reliable, and inexpensive biomarkers. In our pilot studies, we have detected more than 2,000 miRNAs in pooled human CSF and blood plasma samples collected from patients with PD and healthy controls, with the abundance of a subset of these miRNAs differing substantially between PD and control. We therefore hypothesize that miRNAs in human body fluids may serve as good PD biomarkers. To test our hypothesis, we propose to further profile miRNAs in small-pooled human CSF and plasma samples from patients with PD at different stages and healthy and disease controls, using miRNA arrays. Identified miRNA candidates together with those with established relevance to PD will then be further evaluated and confirmed in individual samples using quantitative RT-PCR, with potential confounding factors and correlations between CSF and plasma or between miRNA and known protein marker levels in the same sample considered. This proposed study will establish methodology and foundation for future large- scale validation and longitudinal studies using novel miRNA markers, and may also contribute significantly to the understanding of the roles of miRNAs in PD pathogenesis and development.

Public Health Relevance

Parkinson disease (PD) is a neurodegenerative disorder that afflicts more than one million patients in North America. This project investigates potential microRNA biomarkers in human cerebrospinal fluid and blood plasma to aid in PD diagnosis and disease progression monitoring. Identification of these urgently needed inexpensive and effective biomarkers could greatly enhance PD diagnosis and help assessing the outcome of treatments.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS085425-01A1
Application #
8768667
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Shi, Min; Liu, Changqin; Cook, Travis J et al. (2014) Plasma exosomal ?-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathol 128:639-50