Dataset Information

Proteomics identifies potential biomarkers and implicates the granin family in Parkinson’s disease

ABSTRACT: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Treatments are available to address PD motor symptoms, but not disease progression or cognitive decline. Demonstrating disease modification in clinical trials is still a substantial challenge because of the high disease heterogeneity and variability in progression as well as subjectivity in clinical scoring. To develop novel therapeutics for PD, there is an urgent need to identify biomarkers for patient stratification in clinical trials. In this study, we used cutting edge data-independent acquisition (DIA) mass spectrometry to identify PD-specific biomarkers in patient cerebrospinal fluid (CSF). To identify novel biomarkers with minimal false discovery, two independent cohorts were analyzed by DIA mass spectrometry. An initial discovery cohort of 53 PD and 72 control (CTRL) patient samples was analyzed, identifying 53 proteins with significant changes (nominal p-value ≤ 0.05) in PD relative to CTRL out of the 342 detectable proteins. A second cohort of 28 PD and 43 CTRL samples were analyzed as above and identified 41 proteins with significant changes in PD. Thirteen proteins showed significant changes in both cohorts, some of which are previously reported to be altered in PD (i.e., EPHA4 and SERPINC1). Three members of a specific protein family, which are cleaved into bioactive peptides, were amongst these 13 proteins . Further, peptide-level quantification of the detectable members of this protein family (7 total) revealed that specific regions of all 7 proteins are decreased in Parkinson’s disease samples. Together, these data may implicate altered processing, localization, and/or function of this entire protein family for the first time in PD.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Parkinson's Disease

SUBMITTER: Pablo Sardi

LAB HEAD: Sergio Pablo Sardi

PROVIDER: PXD011216 | Pride | 2020-02-19

REPOSITORIES: Pride

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Cerebrospinal fluid proteomics implicates the granin family in Parkinson's disease.

Rotunno Melissa S MS Lane Monica M Zhang Wenfei W Wolf Pavlina P Oliva Petra P Viel Catherine C Wills Anne-Marie AM Alcalay Roy N RN Scherzer Clemens R CR Shihabuddin Lamya S LS Zhang Kate K Sardi S Pablo SP

Scientific reports 20200212 1

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 ...[more]

PMID: 32051502

Publication: 1/2

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Project description:Parkinson’s disease is second most prevalent neurodegenerative disorder. Parkinson’s disease is hypothesized to be caused by a multifaceted interplay between genetic and environmental factors. We profiled the DNA methylation using the frontal lobe from people who died from Parkinson’s disease and compared them with age-, and sex-matched controls. We hypothesized that the complex regulation of DNA methylation and metabolome leads to deficits that cause irregular motor function among Parkinson’s disease subjects and the metabolomic disparities may reflect the effect of these complex interactions. Herein, we aim to integrate quantitative metabolomics and DNA methylation of brain tissue from primary motor cortex (Brodmann area 4) from Parkinson’s disease sufferers to better understand the biochemistry associated with the onset of the disease. Parkinson’s disease (PD) is second most prevalent neurodegenerative disorder following Alzheimer’s disease. Parkinson’s disease is hypothesized to be caused by a multifaceted interplay between genetic and environmental factors. Herein, and for the first time, we describe the integration of metabolomics and epigenetics (genome-wide DNA methylation; epimetabolomics) to profile the frontal lobe from people who died from PD and compared them with age-, and sex-matched controls. We identified 48 metabolites to be at significantly different concentrations (FDR q<0.05), 4,313 differentially methylated sites [5'-C-phosphate-G-3' (CpGs)] (FDR q<0.05) and increased DNA methylation age in the primary motor cortex of people who died from PD. We identified Primary bile acid biosynthesis as the major biochemical pathway to be perturbed in the frontal lobe of PD sufferers, and the metabolite taurine (p-value = 5.91E-06) as being positively correlated with CpG cg14286187 (SLC25A27; CYP39A1) (FDR q = 0.002), highlighting previously unreported biochemical changes associated with PD pathogenesis. In this novel multi-omics study, we identify regulatory mechanisms which we believe warrant future translational investigation and central biomarkers of PD which require further validation in more accessible biomatrices.

Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

Dataset Information

Proteomics identifies potential biomarkers and implicates the granin family in Parkinson’s disease

Publications

Cerebrospinal fluid proteomics implicates the granin family in Parkinson's disease.

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