PXD047502

PXD047502 is an original dataset announced via ProteomeXchange.

Title	PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons
Description	A GGGGCC repeat expansion in C9orf72 is the most common genetic cause of ALS and FTD (C9ALS/FTD). Dipeptide repeat (DPR) proteins, generated by translation of the expanded repeat, are a major pathogenic feature of C9ALS/FTD pathology, but their physiological impact has yet to be fully determined. Here, we generated C9orf72 DPR knock-in mouse models characterised by expression of 400 codon-optimised polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. This increase in ECM protein levels looked to be a conserved feature of C9ALS/FTD, with a similar signature also present in C9ALS patient iPSC-motor neurons. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human iPSC-neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in C9ALS/FTD patient iPSC motor neurons protected against glutamate-induced cell death. Altogether, our C9orf72 DPR knock-in mice have revealed a neuroprotective and conserved ECM signature in C9ALS/FTD.
HostingRepository	PRIDE
AnnounceDate	2024-03-04
AnnouncementXML	Submission_2024-03-04_06:32:25.713.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Raja Sekhar Nirujogi
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-04 05:05:34	ID requested
⏵ 1	2024-03-04 06:32:27	announced

10.1038/s41593-024-01589-4;

Milioto C, Carcol, é M, Giblin A, Coneys R, Attrebi O, Ahmed M, Harris SS, Lee BI, Yang M, Ellingford RA, Nirujogi RS, Biggs D, Salomonsson S, Zanovello M, de Oliveira P, Katona E, Glaria I, Mikheenko A, Geary B, Udine E, Vaizoglu D, Anoar S, Jotangiya K, Crowley G, Smeeth DM, Adams ML, Niccoli T, Rademakers R, van Blitterswijk M, Devoy A, Hong S, Partridge L, Coyne AN, Fratta P, Alessi DR, Davies B, Busche MA, Greensmith L, Fisher EMC, Isaacs AM, PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons. Nat Neurosci, 27(4):643-655(2024) [pubmed]

submitter keyword: TGF-β, collagen VI, frontotemporal dementia, amyotrophic lateral sclerosis, Proteomics, COL6A1,C9orf72, extracellular matrix

Adrian Isaacs
contact affiliation	UK Dementia Research Institute at UCL, Cruciform Building, Gower Street, London, WC1E 6BT, UK. a.isaacs@ucl.ac.uk.
contact email	a.isaacs@ucl.ac.uk
lab head
Raja Sekhar Nirujogi
contact affiliation	MRC Protein Phosphorylation Unit, university of Dundee
contact email	rnirujogi@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047502
     1. Label: PRIDE project
     2. Name: PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons