Molecular insights into an ancient form of Paget's disease of bone.



Shaw, Barry, Burrell, Carla L, Green, Darrell, Navarro-Martinez, Ana, Scott, Daniel, Daroszewska, Anna ORCID: 0000-0002-6692-6610, van 't Hof, Rob, Smith, Lynn, Hargrave, Frank, Mistry, Sharad
et al (show 10 more authors) (2019) Molecular insights into an ancient form of Paget's disease of bone. Proceedings of the National Academy of Sciences of the United States of America, 116 (21). 10463 - 10472.

[img] Text
Molecular insights into ancient PDB Shaw PNAS 2019.pdf - Published Version

Download (1MB) | Preview

Abstract

Paget's disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals older than 55 y of age. PDB-like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affecting as many as 75% of individual skeletons. Disease prevalence in the remaining collection is high, at least 16% of adults, with age at death estimations as low as 35 y. Despite these atypical features, paleoproteomic analysis identified sequestosome 1 (SQSTM1) or p62, a protein central to the pathological milieu of PDB, as one of the few noncollagenous human sequences preserved in skeletal samples. Targeted proteomic analysis detected >60% of the ancient p62 primary sequence, with Western blotting indicating p62 abnormalities, including in dentition. Direct sequencing of ancient DNA excluded contemporary PDB-associated SQSTM1 mutations. Our observations indicate that the ancient p62 protein is likely modified within its C-terminal ubiquitin-associated domain. Ancient miRNAs were remarkably preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression consistent with that reported in contemporary PDB-associated bone tumors. Our work displays the use of proteomics to inform diagnosis of ancient diseases such as atypical PDB, which has unusual features presumably potentiated by yet-unidentified environmental or genetic factors.

Item Type: Article
Uncontrolled Keywords: Paget's disease, osteosarcoma, p62, SQSTM1, paleoproteomic
Depositing User: Symplectic Admin
Date Deposited: 09 May 2019 12:28
Last Modified: 22 Jan 2021 12:11
DOI: 10.1073/pnas.1820556116
Open Access URL: https://doi.org/10.1073/pnas.1820556116
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3040397