DNA methylation analysis of archival lymphoreticular tissues in Creutzfeldt–Jakob disease

Guntoro, Fernando; Viré, Emmanuelle; Giordani, Chiara; Darwent, Lee; Hummerich, Holger; Linehan, Jacqueline M.; Sinka, Katy; Jaunmuktane, Zane; Brandner, Sebastian; Collinge, John; Mead, Simon

doi:10.1007/s00401-022-02481-w

Cited by 3 publications

(3 citation statements)

References 6 publications

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“…The authors concluded that either additional prevalence studies were needed, as were later carried out, or that more sensitive assays for prions would need to be developed [ 42 ]. More recent studies have attempt to use indirect approaches using methylation array technology to investigate appendix FFPE tissues derived from the Appendix surveys [ 43 ]. However, additional investigations using approaches directly targeting the prion protein may provide insights on the nature of the abnormal PrP detected in the positive samples.…”

Section: Discussionmentioning

confidence: 99%

Conservation of vCJD Strain Properties After Extraction and In Vitro Propagation of PrPSc from Archived Formalin-Fixed Brain and Appendix Tissues Using Highly Sensitive Protein Misfolding Cyclic Amplification

Suleiman,

McGuire,

Chong

et al. 2023

Mol Neurobiol

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Three retrospective lymphoreticular tissue studies (Appendix I, II, and III) aimed to estimate the UK prevalence of variant Creutzfeldt-Jakob disease (vCJD), following exposure of the population to the bovine spongiform encephalopathy (BSE) agent, in the late 1980s and 1990s. These studies evaluated the presence of abnormal prion protein aggregates, in archived formalin-fixed paraffin-embedded (FFPE) appendectomy samples, by immunohistochemical detection. Although there was concordance in the estimated prevalence of vCJD from these studies, the identification of positive specimens from pre- and post-BSE-exposure periods in Appendix III study has raised questions regarding the nature and origin of the detected abnormal prion protein. We applied a robust and novel approach in the extraction of disease-associated prion protein (PrPSc) present in frozen and FFPE samples of brain and appendix from a patient with pathologically confirmed vCJD. The extracted material was used to seed the highly sensitive protein misfolding cyclic amplification assay (hsPMCA) to investigate the in vitro and in vivo propagation properties of the extracted abnormal prion protein. We demonstrate that PrPSc can be successfully extracted from FFPE appendix tissue and propagated in vitro. Bioassay in wild-type and gene-targeted mouse models confirmed that the extracted and amplified product is infectious and retains strain properties consistent with vCJD. This provides a highly sensitive and reliable platform for subsequent analysis of the archived FFPE appendix tissue derived from the Appendix II and III surveys, to further evaluate the nature of the abnormal PrP detected in the positive samples.

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Section: Discussionmentioning

confidence: 99%

Conservation of vCJD Strain Properties After Extraction and In Vitro Propagation of PrPSc from Archived Formalin-Fixed Brain and Appendix Tissues Using Highly Sensitive Protein Misfolding Cyclic Amplification

Suleiman,

McGuire,

Chong

et al. 2023

Mol Neurobiol

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“…Furthermore, another genome-wide methylation study of the CNS of sheep naturally infected with scrapie has identified differentially methylated regions between control and scrapie animals, belonging some of them to genes with possible neuroprotective roles and to genes that may contribute to scrapie disease progression [ 224 ]. Interestingly, a recent study was able to identify different DNA methylation patterns in tonsil and appendix lymphoreticular tissues between sCJD patients and healthy individuals [ 225 ], pointing to a potential source of diagnostic biomarkers in prion diseases.…”

Section: Epigenetic Changes In Prion Diseasesmentioning

confidence: 99%

Epigenetic Changes in Prion and Prion-like Neurodegenerative Diseases: Recent Advances, Potential as Biomarkers, and Future Perspectives

Hernaiz

Toivonen²,

Bolea³

et al. 2022

IJMS

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Prion diseases are transmissible spongiform encephalopathies (TSEs) caused by a conformational conversion of the native cellular prion protein (PrPC) to an abnormal, infectious isoform called PrPSc. Amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases are also known as prion-like diseases because they share common features with prion diseases, including protein misfolding and aggregation, as well as the spread of these misfolded proteins into different brain regions. Increasing evidence proposes the involvement of epigenetic mechanisms, namely DNA methylation, post-translational modifications of histones, and microRNA-mediated post-transcriptional gene regulation in the pathogenesis of prion-like diseases. Little is known about the role of epigenetic modifications in prion diseases, but recent findings also point to a potential regulatory role of epigenetic mechanisms in the pathology of these diseases. This review highlights recent findings on epigenetic modifications in TSEs and prion-like diseases and discusses the potential role of such mechanisms in disease pathology and their use as potential biomarkers.

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“…Although recent studies have shed light on the possible roles of DNA methylation in the pathogenesis of prion diseases [ 24 , 25 , 31 , 32 , 33 ], knowledge in this field is still scarce. Little is known about how 5mC patterns and DNA methylation enzymes behave throughout the course of these diseases and, to the best of our knowledge, no study has yet explored the role of 5hmC in prion pathology.…”

Section: Introductionmentioning

confidence: 99%

5-Methylcytosine and 5-Hydroxymethylcytosine in Scrapie-Infected Sheep and Mouse Brain Tissues

Hernaiz

Sentre

Betancor

et al. 2023

IJMS

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Scrapie is a neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies or prion diseases, which are caused by an infectious isoform of the innocuous cellular prion protein (PrPC) known as PrPSc. DNA methylation, one of the most studied epigenetic mechanisms, is essential for the proper functioning of the central nervous system. Recent findings point to possible involvement of DNA methylation in the pathogenesis of prion diseases, but there is still a lack of knowledge about the behavior of this epigenetic mechanism in such neurodegenerative disorders. Here, we evaluated by immunohistochemistry the 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels in sheep and mouse brain tissues infected with scrapie. Expression analysis of different gene coding for epigenetic regulatory enzymes (DNMT1, DNMT3A, DNMT3B, HDAC1, HDAC2, TET1, and TET2) was also carried out. A decrease in 5mC levels was observed in scrapie-affected sheep and mice compared to healthy animals, whereas 5hmC displayed opposite patterns between the two models, demonstrating a decrease in 5hmC in scrapie-infected sheep and an increase in preclinical mice. 5mC correlated with prion-related lesions in mice and sheep, but 5hmC was associated with prion lesions only in sheep. Differences in the expression changes of epigenetic regulatory genes were found between both disease models, being differentially expressed Dnmt3b, Hdac1, and Tet1 in mice and HDAC2 in sheep. Our results support the evidence that DNA methylation in both forms, 5mC and 5hmC, and its associated epigenetic enzymes, take part in the neurodegenerative course of prion diseases.

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DNA methylation analysis of archival lymphoreticular tissues in Creutzfeldt–Jakob disease

Cited by 3 publications

References 6 publications

Conservation of vCJD Strain Properties After Extraction and In Vitro Propagation of PrPSc from Archived Formalin-Fixed Brain and Appendix Tissues Using Highly Sensitive Protein Misfolding Cyclic Amplification

Conservation of vCJD Strain Properties After Extraction and In Vitro Propagation of PrPSc from Archived Formalin-Fixed Brain and Appendix Tissues Using Highly Sensitive Protein Misfolding Cyclic Amplification

Epigenetic Changes in Prion and Prion-like Neurodegenerative Diseases: Recent Advances, Potential as Biomarkers, and Future Perspectives

5-Methylcytosine and 5-Hydroxymethylcytosine in Scrapie-Infected Sheep and Mouse Brain Tissues

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