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Title: An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression

Abstract

Aim: The alpha-synuclein (α-syn) level in human cerebrospinal fluid (CSF), as measured by immunoassays, is promising as a Parkinson’s disease (PD) biomarker. However, the levels of total α-syn are inconsistent among studies with large cohorts and different measurement platforms. Total α-syn level also does not correlate with disease severity or progression. Here, we developed a highly sensitive Multiple Reaction Monitoring (MRM) method to measure absolute CSF α-syn peptide concentrations without prior enrichment or fractionation, aiming to discover new candidate biomarkers. Results: Six peptides covering 73% of protein sequence were reliably identified, and two were consistently quantified in cross-sectional and longitudinal cohorts. Absolute concentration of α-syn in human CSF was determined to be 2.1ng/mL. A unique α-syn peptide, TVEGAGSIAAATGFVK (81-96), displayed excellent correlation with previous immunoassay results in two independent PD cohorts (p < 0.001), correlated with disease severity, and its changes significantly tracked the disease progression longitudinally. Conclusions: An MRM assay to quantify human CSF α-syn was developed and optimized. Sixty clinical samples from cross-sectional and longitudinal PD cohorts were analyzed with this approach. Although further larger-scale validation is needed, the results suggest that α-syn peptide could serve as a promising biomarker in PD diagnosis and progression.

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1];  [1];  [1];  [3];  [3];  [4];  [5];  [6]; ORCiD logo [7]
  1. Department of Pathology, University of Washington, Seattle WA USA
  2. Department of Pathology, University of Washington, Seattle WA USA; Department of Pathology, No. 3 Hospital of Beijing University, Beijing China
  3. Pacific Northwest National Laboratory, Richland WA USA
  4. Parkinson's Disease Research and Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle WA USA; Department of Neurology, University of Washington School of Medicine, Seattle WA USA
  5. Department of Neurology, University of Washington School of Medicine, Seattle WA USA
  6. Department of Neurology, Oregon Health and Science University, Portland OR USA
  7. Department of Pathology, University of Washington, Seattle WA USA; Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing 100083 China
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1378039
Report Number(s):
PNNL-SA-124743
Journal ID: ISSN 1862-8346; WN9030198
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: PROTEOMICS - Clinical Applications; Journal Volume: 11; Journal Issue: 7-8
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; parkinson’s disease; SRM; a-syn; diagnosis; progression

Citation Formats

Yang, Li, Stewart, Tessandra, Shi, Min, Pottiez, Gwenael, Dator, Romel, Wu, Rui, Aro, Patrick, Schuster, Robert J., Ginghina, Carmen, Pan, Catherine, Gao, Yuqian, Qian, Weijun, Zabetian, Cyrus P., Hu, Shu-Ching, Quinn, Joseph F., and Zhang, Jing. An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression. United States: N. p., 2017. Web. doi:10.1002/prca.201700045.
Yang, Li, Stewart, Tessandra, Shi, Min, Pottiez, Gwenael, Dator, Romel, Wu, Rui, Aro, Patrick, Schuster, Robert J., Ginghina, Carmen, Pan, Catherine, Gao, Yuqian, Qian, Weijun, Zabetian, Cyrus P., Hu, Shu-Ching, Quinn, Joseph F., & Zhang, Jing. An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression. United States. doi:10.1002/prca.201700045.
Yang, Li, Stewart, Tessandra, Shi, Min, Pottiez, Gwenael, Dator, Romel, Wu, Rui, Aro, Patrick, Schuster, Robert J., Ginghina, Carmen, Pan, Catherine, Gao, Yuqian, Qian, Weijun, Zabetian, Cyrus P., Hu, Shu-Ching, Quinn, Joseph F., and Zhang, Jing. Wed . "An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression". United States. doi:10.1002/prca.201700045.
@article{osti_1378039,
title = {An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression},
author = {Yang, Li and Stewart, Tessandra and Shi, Min and Pottiez, Gwenael and Dator, Romel and Wu, Rui and Aro, Patrick and Schuster, Robert J. and Ginghina, Carmen and Pan, Catherine and Gao, Yuqian and Qian, Weijun and Zabetian, Cyrus P. and Hu, Shu-Ching and Quinn, Joseph F. and Zhang, Jing},
abstractNote = {Aim: The alpha-synuclein (α-syn) level in human cerebrospinal fluid (CSF), as measured by immunoassays, is promising as a Parkinson’s disease (PD) biomarker. However, the levels of total α-syn are inconsistent among studies with large cohorts and different measurement platforms. Total α-syn level also does not correlate with disease severity or progression. Here, we developed a highly sensitive Multiple Reaction Monitoring (MRM) method to measure absolute CSF α-syn peptide concentrations without prior enrichment or fractionation, aiming to discover new candidate biomarkers. Results: Six peptides covering 73% of protein sequence were reliably identified, and two were consistently quantified in cross-sectional and longitudinal cohorts. Absolute concentration of α-syn in human CSF was determined to be 2.1ng/mL. A unique α-syn peptide, TVEGAGSIAAATGFVK (81-96), displayed excellent correlation with previous immunoassay results in two independent PD cohorts (p < 0.001), correlated with disease severity, and its changes significantly tracked the disease progression longitudinally. Conclusions: An MRM assay to quantify human CSF α-syn was developed and optimized. Sixty clinical samples from cross-sectional and longitudinal PD cohorts were analyzed with this approach. Although further larger-scale validation is needed, the results suggest that α-syn peptide could serve as a promising biomarker in PD diagnosis and progression.},
doi = {10.1002/prca.201700045},
journal = {PROTEOMICS - Clinical Applications},
number = 7-8,
volume = 11,
place = {United States},
year = {Wed Apr 19 00:00:00 EDT 2017},
month = {Wed Apr 19 00:00:00 EDT 2017}
}