Dataset Information

Metabolic Profiling of CSF from People Suffering from Sporadic and LRRK2 Parkinson's Disease: A Pilot Study

ABSTRACT: CSF from unique groups of Parkinson's disease (PD) patients was biochemically profiled to identify previously unreported metabolic pathways linked to PD pathogenesis, and novel biochemical biomarkers of the disease were characterized. Utilizing both 1H NMR and DI-LC-MS/MS we quantitatively profiled CSF from patients with sporadic PD (n = 20) and those who are genetically predisposed (LRRK2) to the disease (n = 20), and compared those results with age and gender-matched controls (n = 20). Further, we systematically evaluated the utility of several machine learning techniques for the diagnosis of PD. 1H NMR and mass spectrometry-based metabolomics, in combination with bioinformatic analyses, provided useful information highlighting previously unreported biochemical pathways and CSF-based biomarkers associated with both sporadic PD (sPD) and LRRK2 PD. Results of this metabolomics study further support our group's previous findings identifying bile acid metabolism as one of the major aberrant biochemical pathways in PD patients. This study demonstrates that a combination of two complimentary techniques can provide a much more holistic view of the CSF metabolome, and by association, the brain metabolome. Future studies for the prediction of those at risk of developing PD should investigate the clinical utility of these CSF-based biomarkers in more accessible biomatrices. Further, it is essential that we determine whether the biochemical pathways highlighted here are recapitulated in the brains of PD patients with the aim of identifying potential therapeutic targets.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR) -

SUBMITTER: Ali Yilmaz

PROVIDER: MTBLS863 | MetaboLights | 2022-09-02

REPOSITORIES: MetaboLights

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Metabolic Profiling of CSF from People Suffering from Sporadic and LRRK2 Parkinson's Disease: A Pilot Study.

Yilmaz Ali A Ugur Zafer Z Ustun Ilyas I Akyol Sumeyya S Bahado-Singh Ray O RO Maddens Michael M Aasly Jan O JO Graham Stewart F SF

Cells 20201031 11

CSF from unique groups of Parkinson's disease (PD) patients was biochemically profiled to identify previously unreported metabolic pathways linked to PD pathogenesis, and novel biochemical biomarkers of the disease were characterized. Utilizing both 1H NMR and DI-LC-MS/MS we quantitatively profiled CSF from patients with sporadic PD (n = 20) and those who are genetically predisposed (LRRK2) to the disease (n = 20), and compared those results with age and gender-matched c ...[more]

PMID: 33142859

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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.

			Action	DRS
	MTBLS863	Other
	FILES	Other
	a_MTBLS863_NMR___metabolite_profiling.txt	Txt
	files-all.json	Other
	i_Investigation.txt	Txt