Molecular insights into an ancient form of Paget's disease of bone.pdf (1.21 MB)
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Molecular insights into an ancient form of Paget's disease of bone.

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posted on 27.08.2019, 08:33 by B Shaw, CL Burrell, D Green, A Navarro-Martinez, D Scott, A Daroszewska, R van 't Hof, L Smith, F Hargrave, S Mistry, A Bottrill, BM Kessler, R Fischer, A Singh, T Dalmay, WD Fraser, K Henneberger, T King, S Gonzalez, R Layfield
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.

Funding

We thank the Trustees of Norton Priory Museum Trust for providing access to skeletal samples and for providing Fig. 1F; Paul Quigley for help with photography; and Mark Benson, Chloe Cooper, and Irina Mohorianu for contributions to preliminary work. This work was supported by The Wellcome Trust Grant 107720/Z/15/Z and the Paget’s Association, Michael Davie Research Foundation, Big C, University of East Anglia, and University of Nottingham.

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Citation

Proceedings of the National Academy of Sciences U. S. A., 2019, 116 (21), pp. 10463-10472

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome Biology

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VoR (Version of Record)

Published in

Proceedings of the National Academy of Sciences U. S. A.

Publisher

National Academy of Sciences

eissn

1091-6490

Acceptance date

26/03/2019

Copyright date

2019

Available date

27/08/2019

Publisher version

https://www.pnas.org/content/116/21/10463

Notes

Data deposition: Proteomic data reported in this paper have been deposited in ProteomeXchange (accession no. PXD011743). The sequencing data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession nos. GSE87021 and GSE118540). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820556116/-/DCSupplemental.

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en

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