PXD011743-1

PXD011743 is an original dataset announced via ProteomeXchange.

Title	Molecular insights into an ancient form of Paget disease of bone
Description	Paget disease of bone (PDB) is a chronic skeletal disorder with contemporary cases characterised by one or a few affected bones in individuals over 55 years of age. PDB-like changes have been noted in archaeological remains as old as Roman although accurate diagnoses and knowledge of the natural history of ancient forms of the disease are lacking. Previous macroscopic and radiographic analyses of six skeletons from a collection of 130 excavated at Norton Priory in Cheshire, UK, and dating to late Medieval times, noted unusually extensive pathological changes resembling PDB affecting up to 75% of individual skeletons. Here we report the prevalence of the disease in the collection is also remarkably high (at least 15.8% of the adult sample) with age-at-death estimations as low as 35 years. Despite these profound phenotypic differences paleoproteomic analyses identified SQSTM1/p62 (p62), a protein central to the pathological milieu of classical PDB, as one of the few non-collagenous human sequences preserved in skeletal samples, indicating that the disorder was likely an ancient precursor of contemporary PDB. Western blotting indicated abnormal migration of ancient p62 protein, with subsequent targeted proteomic analyses detecting more than 60% of the p62 primary sequence and directing sequencing analyses of ancient DNA that excluded contemporary PDB-associated SQSTM1 mutations. Together our observations indicate the ancient p62 protein is likely modified within its C-terminal ubiquitin-associated (UBA) domain. Ancient miRNAs were also remarkably well preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression changes consistent with that reported in contemporary PDB-associated bone tumours. Our work demonstrates the potential of proteomics to inform diagnoses of ancient disease and supports the proposal that Medieval Norton Priory was a ‘hotspot’ for an ancient form of PDB, with unusual features presumably potentiated by as yet unidentified environmental or genetic factors.
HostingRepository	PRIDE
AnnounceDate	2019-04-09
AnnouncementXML	Submission_2019-04-09_02:39:55.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD011743
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Roman Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Ammonia-loss; Crotonaldehyde; Amidated; LG-pyrrole; Oxidation; Ethanolyl; Carboxy; Propionamide; Didehydro; Deamidated; Pro->Pyrrolidinone; Acetyl; Deoxy; Malonyl; Methyl+Deamidated; Carboxymethyl; Formyl; Carbamyl; Lys->Allysine; Glycosyl; Carbamidomethyl; Gln->pyro-Glu; Amidine; Glu->pyro-Glu; Dehydrated; Biotin; Carboxyethyl; Dioxidation; Pro->Pyrrolidone
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2018-11-19 08:38:40	ID requested
⏵ 1	2019-04-09 02:39:56	announced
2	2019-05-06 09:02:19	announced	Updated publication reference for PubMed record(s): 31036632.

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: paleoproteomics, paget disease, SQSTM1, p62, osteosarcoma

Roman Fischer
contact affiliation	Target Discovery Institute Discovery Proteomics Facility
contact email	roman.fischer@ndm.ox.ac.uk
lab head
Roman Fischer
contact affiliation	University of Oxford
contact email	roman.fischer@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD011743
     1. Label: PRIDE project
     2. Name: Molecular insights into an ancient form of Paget disease of bone