Cerebrospinal fluid proteomics implicates the granin family in Parkinson’s disease

Melissa S. Rotunno, Monica Lane, Wenfei Zhang, Pavlina Wolf, Petra Oliva, Catherine Viel, Anne Marie Wills, Roy N. Alcalay, Clemens R. Scherzer, Lamya S. Shihabuddin, Kate Zhang, S. Pablo Sardi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Parkinson’s disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Better understanding of the underlying disease mechanism(s) is an urgent need for the development of disease-modifying therapeutics. Limited studies have been performed in large patient cohorts to identify protein alterations in cerebrospinal fluid (CSF), a proximal site to pathology. We set out to identify disease-relevant protein changes in CSF to gain insights into the etiology of Parkinson’s disease and potentially assist in disease biomarker identification. In this study, we used liquid chromatography-tandem mass spectrometry in data-independent acquisition (DIA) mode to identify Parkinson’s-relevant biomarkers in cerebrospinal fluid. We quantified 341 protein groups in two independent cohorts (n = 196) and a longitudinal cohort (n = 105 samples, representing 40 patients) consisting of Parkinson’s disease and healthy control samples from three different sources. A first cohort of 53 Parkinson’s disease and 72 control samples was analyzed, identifying 53 proteins with significant changes (p < 0.05) in Parkinson’s disease relative to healthy control. We established a biomarker signature and multiple protein ratios that differentiate Parkinson’s disease from healthy controls and validated these results in an independent cohort. The second cohort included 28 Parkinson’s disease and 43 control samples. Independent analysis of these samples identified 41 proteins with significant changes. Evaluation of the overlapping changes between the two cohorts identified 13 proteins with consistent and significant changes (p < 0.05). Importantly, we found the extended granin family proteins as reduced in disease, suggesting a potential common mechanism for the biological reduction in monoamine neurotransmission in Parkinson’s patients. Our study identifies several novel protein changes in Parkinson’s disease cerebrospinal fluid that may be exploited for understanding etiology of disease and for biomarker development.

Original languageEnglish
Article number2479
JournalScientific Reports
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2020
Externally publishedYes

Funding

FundersFunder number
A.L.S. Association
American Parkinson’s Disease Association
Massachusetts Alzheimer’s Disease Research Center NIAP50AG005134
Parkinson’s Foundation
Proteome Sciences
Sanofi/Genzyme
National Institutes of HealthR01AG057331
U.S. Department of Defense
National Institute of Neurological Disorders and StrokeU01NS100603, U01NS082157, U01NS095736
Michael J. Fox Foundation for Parkinson's Research
Harvard NeuroDiscovery Center
Bristol-Myers Squibb
Pfizer
Sanofi
Biogen
American Parkinson Disease Association

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