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, the authors developed a highly sensitive 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 2.1 ng/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.
Bibliographical noteFunding Information:
This work was supported by LEAPS grant from the Michael J. Fox Foundation, and partially by Parkinson's Disease Foundation (PDF-FBS-1552), National Institute of Neurological Disorders and Stroke (5U01NS082137-04 and U01 NS091272-01A1), National Institutes of Health (P50 NS062684, R01 NS065070), and University of Washington's Proteomics Resource (UWPR95794).
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
- Parkinson's disease
- alpha-synuclein (α-syn)