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

Barry Shaw, Carla Burrell, Darrell Green, Ana Navarro-Martinez, Daniel Scott, Ana Daroszewska, Rob van't Hof, Lynn Smith, Frank Hargrave, Sharad Mistry, Andrew Bottrill, Benedikt Kessler, Roman Fisher, Archana Singh, Tamas Dalmay, William Fraser, Kristin Henneberger, Turi King, Silvia Gonzalez, Robert Layfield

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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.
Original languageEnglish
Pages (from-to)10463-10472
JournalProceedings of the National Academy of Sciences of the United States of America (PNAS)
Volume116
Issue number21
Early online date29 Apr 2019
DOIs
Publication statusPublished - 21 May 2019

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