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



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.



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.
Department of Pathology, University of Washington, Seattle, WA, USA.
Li
L
Yang
Department of Pathology, University of Washington, Seattle, WA, USA.
Tessandra
T
Stewart
Department of Pathology, University of Washington, Seattle, WA, USA.
Min
M
Shi
Department of Pathology, University of Washington, Seattle, WA, USA.
Gwenael
G
Pottiez
Department of Pathology, University of Washington, Seattle, WA, USA.
Romel
R
Dator
Department of Pathology, University of Washington, Seattle, WA, USA.|Department of Pathology, No. 3 Hospital of Beijing University, Beijing, China.
Rui
R
Wu
Department of Pathology, University of Washington, Seattle, WA, USA.
Patrick
P
Aro
Department of Pathology, University of Washington, Seattle, WA, USA.
Robert J
RJ
Schuster
Department of Pathology, University of Washington, Seattle, WA, USA.
Carmen
C
Ginghina
Department of Pathology, University of Washington, Seattle, WA, USA.
Catherine
C
Pan
Pacific Northwest National Laboratory, Richland, WA, USA.
Yuqian
Y
Gao
Pacific Northwest National Laboratory, Richland, WA, USA.
Weijun
W
Qian
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.
Cyrus P
CP
Zabetian
Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
Shu-Ching
SC
Hu
Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
Joseph F
JF
Quinn
Department of Pathology, University of Washington, Seattle, WA, USA.|Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing, 100083, China.
Jing
0000-0002-3656-1112
J
Zhang
D000328:Adult; D000368:Aged; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D051844:alpha-Synuclein / Q000134:cerebrospinal fluid*
D051844:alpha-Synuclein
Diagnosis; MRM; Parkinson's disease; Progression; alpha-synuclein (α-syn)