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Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define putative diagnostic biosignatures for Parkinson’s disease

ABSTRACT: Background: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been recognized as genetic risk factors for Parkinson’s disease (PD). However, compared to cancer, fewer genetic mutations contribute to the cause of PD, propelling the search for protein biomarkers for early detection of the disease. Methods: Utilizing 138 urine samples from four groups, healthy individuals (control), healthy individuals with G2019S mutation in the LRRK2 gene (non-manifesting carrier/NMC), PD individuals without G2019S mutation (idiopathic PD/iPD), and PD individuals with G2019S mutation (LRRK2 PD), we applied a proteomics strategy to determine potential diagnostic biomarkers for PD from urinary extracellular vesicles (EVs). Results: After efficient isolation of urinary EVs through chemical affinity followed by mass spectrometric analyses of EV peptides and enriched phosphopeptides, we identify and quantify 4476 unique proteins and 2680 unique phosphoproteins. We detect multiple proteins and phosphoproteins elevated in PD EVs that are known to be involved in important PD pathways, in particular the autophagy pathway, as well as neuronal cell death, neuroinflammation, and formation of amyloid fibrils. We establish a panel of proteins and phosphoproteins as novel candidates for disease biomarkers and substantiate the biomarkers using machine learning, ROC, clinical correlation, and in-depth network analysis. Several putative disease biomarkers are further partially validated in patients with PD using parallel reaction monitoring (PRM) and immunoassay for targeted quantitation. Conclusions: These findings demonstrate a general strategy of utilizing biofluid EV proteome/phosphoproteome as an outstanding and non-invasive source for a wide range of disease exploration.

ORGANISM(S): Homo Sapiens

SUBMITTER: Marco Hadisurya

PROVIDER: PXD032175 | panorama | Sat Nov 02 00:00:00 GMT 2024

REPOSITORIES: PanoramaPublic

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Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define putative diagnostic biosignatures for Parkinson's disease.

Hadisurya Marco M Li Li L Kuwaranancharoen Kananart K Wu Xiaofeng X Lee Zheng-Chi ZC Alcalay Roy N RN Padmanabhan Shalini S Tao W Andy WA Iliuk Anton A

Communications medicine 20230510 1

<h4>Background</h4>Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been recognized as genetic risk factors for Parkinson's disease (PD). However, compared to cancer, fewer genetic mutations contribute to the cause of PD, propelling the search for protein biomarkers for early detection of the disease.<h4>Methods</h4>Utilizing 138 urine samples from four groups, healthy individuals (control), healthy individuals with G2019S mutation in the LRRK2 gene (non-manifesting carrier/NMC), ...[more]

PMID: 37165152

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Project description:Parkinson’s disease (PD) is a prevalent and incurable neurodegenerative disease for which robust biomarkers for early detection and tailored treatment are needed. Protein abundance measurements have so far not proven discriminative as PD biomarkers. Since alterations in protein structure reflect various functionally relevant molecular events, such as allostery, chemical modification, protein misfolding or molecular interaction, we have tested whether global analysis of protein structural changes is informative about PD pathophysiology and status and could form the basis of the new concept of structural biomarkers of disease. We applied limited proteolysis-mass spectrometry (LiP-MS) for the detection of global protein structural changes in cerebrospinal fluid (CSF) of PD patients and age-matched healthy individuals. Using linear modeling to correct for covariates, we identified 76 proteins as structurally altered in the CSF of patients with PD. We identified structural alterations in several proteins implicated in PD, many of which were also structurally altered in PD brain tissue suggesting that this approach provides insight into pathological mechanisms, although validation in independent cohorts is needed. Protein structural information from CSF outperformed protein abundance information in discriminating between healthy and PD subjects. Further, candidate structural biomarkers from our screen provided complementary information to CSF measures of the hallmark PD protein α-synuclein and thus improved the sensitivity and specificity of discriminating the healthy and PD states. Finally, we present the first analysis of inter-individual variability of a structural proteome in healthy humans, identifying biophysical and structural features of variable and invariable protein regions. Structurally variable protein regions show a greater propensity for protein-protein interaction and higher disorder than non-variable peptides. This dataset will be a valuable resource for structural biology and for future structure-based biomarker research. Our data suggest that global analyses of the human structural proteome will lead to the discovery of novel, structural biomarkers of disease and enables hypothesis-generation about the molecular events underlying disease processes.

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Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define putative diagnostic biosignatures for Parkinson’s disease

Publications

Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define putative diagnostic biosignatures for Parkinson's disease.

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