Molecular insights into an ancient form of Paget’s disease of bone

Shaw, Barry, Burrell, Carla, Green, Darrell ORCID: https://orcid.org/0000-0002-0217-3322, Navarro-Martinez, Ana, Scott, Daniel, Daroszewska, Ana, van't Hof, Rob, Smith, Lynn, Hargrave, Frank, Mistry, Sharad, Bottrill, Andrew, Kessler, Benedikt, Fisher, Roman, Singh, Archana, Dalmay, Tamas ORCID: https://orcid.org/0000-0003-1492-5429, Fraser, William, Henneberger, Kristin, King, Turi, Gonzalez, Silvia and Layfield, Robert (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 (PNAS), 116 (21). pp. 10463-10472. ISSN 1091-6490

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Abstract

Paget’s disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals over 55 years 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 up to 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 years. 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 non-collagenous 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 (UBA) domain. Ancient microRNAs 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 tumours. Our work displays the use of proteomics to inform diagnosis of ancient disease such as atypical PDB, which has unusual features presumably potentiated by as yet unidentified environmental or genetic factors.

Item Type:	Article
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Science > Research Groups > Plant Sciences Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	29 Mar 2019 16:30
Last Modified:	19 Oct 2023 02:24
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70389
DOI:	10.1073/pnas.1820556116

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