PXD034120

PXD034120 is an original dataset announced via ProteomeXchange.

Title	Global, in situ analysis of the structural proteome in individuals with Parkinson’s disease to identify a new class of biomarker
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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:17:38.881.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marie-Therese Mackmull
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-25 06:55:01	ID requested
1	2022-10-27 05:06:57	announced
2	2023-05-14 15:06:32	announced	2023-05-14: Updated project metadata.
⏵ 3	2023-11-14 08:17:39	announced	2023-11-14: Updated project metadata.

Mackmull MT, Nagel L, Sesterhenn F, Muntel J, Grossbach J, Stalder P, Bruderer R, Reiter L, van de Berg WDJ, de Souza N, Beyer A, Picotti P, Global, in situ analysis of the structural proteome in individuals with Parkinson's disease to identify a new class of biomarker. Nat Struct Mol Biol, 29(10):978-989(2022) [pubmed]

ProteomeXchange project tag: EPIC-XS

submitter keyword: Human, Parkinson Disease, CSF, structural proteomics, LC-MS/MS

Paola Picotti
contact affiliation	Institute of Molecular Systems Biology Otto-​Stern-Weg 3 8093 Zürich Switzerland
contact email	picotti@imsb.biol.ethz.ch
lab head
Marie-Therese Mackmull
contact affiliation	ETHZ
contact email	mackmull@imsb.biol.ethz.ch
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/10/PXD034120

PRIDE project URI

• PRIDE
  1. PXD034120
     1. Label: PRIDE project
     2. Name: Global, in situ analysis of the structural proteome in individuals with Parkinson’s disease to identify a new class of biomarker