PXD051859-1

PXD051859 is an original dataset announced via ProteomeXchange.

Title	Elevated cerebrospinal fluid ubiquitin carboxyl-terminal hydrolase isozyme L1 in asymptomatic C9orf72 hexanucleotide repeat expansion carriers
Description	Importance: An intronic hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest monogenic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Predicting those who will develop neurodegeneration and its timing will be essential to initiating and assessing preventative therapy. This requires consideration of both compensatory, protective mechanisms and pathogenic events prior to overt neurodegeneration. Objective: To identify biochemical changes in individuals at higher risk of developing ALS or FTD via C9orf72 HRE heterozygosity. Design: Cross sectional observational study. Setting: Tertiary ALS or dementia referral centre. Participants: People with established ALS or FTD, either due to C9orf72 HRE or apparently sporadic cases; asymptomatic first-degree relatives of those with a known C9orf72 HRE; asymptomatic non-carrier controls. Exposure: C9orf72 HRE. Main outcomes: Relative abundance of 30 predefined cerebrospinal fluid biomarkers of ALS and FTD comparing asymptomatic C9orf72 HRE carriers and age-matched non-carriers. Differential abundance of proteins quantified using data independent acquisition mass spectrometry and neurofilament light chain measured by electrochemiluminescent assay. Results: Data for 19 people with sporadic ALS, 10 people with C9orf72 ALS, 14 people with sporadic FTD, 10 people with C9orf72 FTD, 48 asymptomatic C9orf72 HRE carriers and 39 non-carrier controls were analysed. Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034). Neurofilament light chain levels did not differ significantly between groups. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after exclusion of those with high neurofilament light chain levels, after adjusting for NFL level and after adjusting for age. Conclusions and relevance: Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 hexanucleotide repeat expansion carriers occurs in the absence of elevation in neurofilament light chain, potentially reflecting mechanisms that precede the phase of neurodegeneration characterised by rapid neuronal loss. Such mechanisms may have either compensatory or pathogenic roles. Ubiquitin carboxyl-terminal hydrolase isozyme L1 elevation brings forward the window on the changes associated with the C9orf72 HRE carrier state, with the potential to inform understanding penetrance and approaches to prevention.
HostingRepository	PRIDE
AnnounceDate	2024-11-19
AnnouncementXML	Submission_2024-11-19_05:46:36.999.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; iodoacetamide derivatized residue
Instrument	Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-29 13:52:42	ID requested
⏵ 1	2024-11-19 05:46:37	announced

10.1002/ANA.27133;

submitter keyword: CSF

amyotrophic lateral sclerosis

frontotemporal dementia

biomarker

mass spectrometry

proteomics

C9orf72

UCHL1.

Dr Alexander G 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. PXD051859
     1. Label: PRIDE project
     2. Name: Elevated cerebrospinal fluid ubiquitin carboxyl-terminal hydrolase isozyme L1 in asymptomatic C9orf72 hexanucleotide repeat expansion carriers