PXD044274-1

PXD044274 is an original dataset announced via ProteomeXchange.

Title	Data-independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis
Description	Unbiased proteomics of human cerebrospinal fluid (CSF) has been used successfully to identify biomarkers of Amyotrophic Lateral Sclerosis (ALS). However, high abundance proteins mask the presence of lower abundance proteins that may hold valuable diagnostic and prognostic use. Developments in mass spectrometry proteomic data acquisition methods therefore hold promise for improved protein depth and more sensitive biomarker discovery. In this study, mass spectrometry with library-free data-independent acquisition (DIA) was used to compare the CSF proteome of 40 people with ALS, 15 healthy controls and 8 people with mimicking conditions. Qthen quantified protein groups were subsequently correlated with clinical variables. Univariate analysis identified 7 proteins significantly upregulated in ALS vs healthy controls, and 9 with altered abundance in ALS vs mimicking conditions (FDR <0.1). Elevated Chitotriosidase 1 (CHIT1) was common to both comparisons and showed strong correlation with disease progression rate (Pearson r =0.41, FDR-adjusted p = 0.035), but no association with survival (Pearson correlation and Kaplan-Meier survival analysis). Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1; upregulated in ALS vs healthy controls) showed a stronger correlation with disease progression rate (Pearson r = 0.53, FDR-adjusted p = 0.003) and significant association with survival in Kaplan Meier analysis (log rank p = 0.013) but no independent effect in proportional hazards models. Weighted correlation network analysis was then used to identify functionally relevant modules of proteins. One module, enriched for inflammatory functions, was strongly associated with age at disease onset (Pearson r = 0.58, FDR-adjusted p = 0.005) and survival (Hazard Ratio 1.78, FDR = 0.065), and a second module, enriched for endoplasmic reticulum proteins, negatively correlated with disease progression rate (r = -0.42, FDR-adjusted p =0.109). This study confirms that UCHL1 is strongly associated with disease progression and survival, and highlights potential of inflammatory and endoplasmic reticulum proteins to provide prognostic biomarker potential.
HostingRepository	PRIDE
AnnounceDate	2024-05-21
AnnouncementXML	Submission_2024-05-21_12:43:55.433.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	iolanda Vendrell
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-01 17:45:44	ID requested
⏵ 1	2024-05-21 12:43:56	announced

10.1111/jnc.16030;

Dellar ER, Vendrell I, Talbot K, Kessler BM, Fischer R, Turner MR, Thompson AG, Data-independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis. J Neurochem, 168(2):115-127(2024) [pubmed]

submitter keyword: Amyotrophic Lateral Sclerosis, DIA, CSF, Mass spectrometry, Proteomics, Biomarker

Alexander Thompson
contact affiliation	Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
contact email	alexander.thompson@ndcn.ox.ac.uk
lab head
iolanda Vendrell
contact affiliation	Target Discovery Institute, NDMRB
contact email	iolanda.vendrell@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044274
     1. Label: PRIDE project
     2. Name: Data-independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis