PXD024594

PXD024594 is an original dataset announced via ProteomeXchange.

Title	Protein aggregation is an early manifestation of phospholamban p.(Arg14del)-related cardiomyopathy
Description	Background: The p.(Arg14del) pathogenic variant (R14del) of the phospholamban (PLN) gene is a prevalent cause of cardiomyopathy with heart failure. The exact underlying pathophysiology is unknown, and a suitable therapy is unavailable. We aim to identify molecular perturbations underlying this cardiomyopathy in a clinically relevant PLN-R14del mouse model. Methods: We investigated progression of cardiomyopathy in PLN-R14∆/∆ mice using echocardiography, electrocardiography and histological tissue analysis. RNA sequencing and mass spectrometry were performed on cardiac tissues at 3 weeks of age (before onset of disease), 5 weeks, when mild cardiomyopathy has developed, and 8 weeks (end-stage). Data were compared with cardiac expression levels of mice that underwent myocardial ischemia-reperfusion or myocardial infarction surgery, in an effort to identify alterations that are specific to PLN-R14del-related cardiomyopathy. Results: At 3 weeks of age, PLN-R14∆/∆ mice had normal cardiac function, but from the age of 4 weeks, we observed increased myocardial fibrosis and impaired global longitudinal strain. From 5 weeks onwards, ventricular dilatation, decreased contractility and diminished ECG voltages were observed. Strikingly, PLN protein aggregation was present prior to onset of functional deficits. Transcriptomics and proteomics revealed differential regulation of processes involved in remodelling, inflammation and metabolic dysfunction, in part similar to ischemic cardiomyopathy. Protein homeostasis pathways were identified exclusively in PLN-R14∆/∆ mice, even before disease onset, in concert with aggregate formation. Conclusions: We mapped the development of PLN-R14del-related cardiomyopathy, and identified alterations in proteostasis and PLN protein aggregation amongst the first manifestations of this disease, which could possibly be a novel target for therapy.
HostingRepository	PRIDE
AnnounceDate	2021-11-03
AnnouncementXML	Submission_2021-11-03_02:49:36.938.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD024594
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Xiaoke Yin
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-08 23:25:52	ID requested
⏵ 1	2021-11-03 02:49:37	announced

Eijgenraam TR, Boogerd CJ, Stege NM, Oliveira Nunes Teixeira V, Dokter MM, Schmidt LE, Yin X, Theofilatos K, Mayr M, van der Meer P, van Rooij E, van der Velden J, Sillj, é HHW, de Boer RA, Protein Aggregation Is an Early Manifestation of Phospholamban p.(Arg14del)-Related Cardiomyopathy: Development of PLN-R14del-Related Cardiomyopathy. Circ Heart Fail, 14(11):e008532(2021) [pubmed]

submitter keyword: phospholamban, inherited cardiomyopathy, heart failure, protein aggregation

Manuel Mayr
contact affiliation	King's BHF Centre, King's College London, London, UK
contact email	manuel.mayr@kcl.ac.uk
lab head
Xiaoke Yin
contact affiliation	Cardiovascular Division, King's College London
contact email	xiaoke.yin@kcl.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024594
     1. Label: PRIDE project
     2. Name: Protein aggregation is an early manifestation of phospholamban p.(Arg14del)-related cardiomyopathy