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Distribution of microRNA profiles in pre-clinical and clinical forms of murine and human prion disease

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journal contribution
posted on 22.04.2021, 23:47 by Lesley Sim, C Quek, Xia Li, SA Bellingham, LJ Ellett, Mitch Shambrook, S Zafar, I Zerr, VA Lawson, Andrew Hill
Prion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration. In the pre-clinical stage, we hypothesize that upon prion infection, transcriptional changes occur that can lead to early neurodegeneration. A longitudinal analysis of miRNAs in pre-clinical and clinical forms of murine prion disease demonstrated dynamic expression changes during disease progression in the affected thalamus region and serum. Serum samples at each timepoint were collected whereby extracellular vesicles (EVs) were isolated and used to identify blood-based biomarkers reflective of pathology in the brain. Differentially expressed EV miRNAs were validated in human clinical samples from patients with human sporadic Creutzfeldt-Jakob disease (sCJD), with the molecular subtype at codon 129 either methionine-methionine (MM, n = 14) or valine-valine (VV, n = 12) compared to controls (n = 20). EV miRNA biomarkers associated with prion infection predicted sCJD with an AUC of 0.800 (85% sensitivity and 66.7% specificity) in a second independent validation cohort (n = 26) of sCJD and control patients with MM or VV subtype. This study discovered clinically relevant miRNAs that benefit diagnostic development to detect prion-related diseases and therapeutic development to inhibit prion infectivity.

Funding

This study was funded by the National Health and Medical Research Council of Australia (to A.F.H GNT1002349; GNT1041413; GNT1132604) and the Australian CJD Support Group Network Memorial Award in memory of Lorraine Seabrook. L.C. was awarded the 2019 Australian CJD Support Group Network Memorial Award in memory of Adrian Chesterton, Norma Crawley and Danilo Banzon. I.Z. received funds by the Robert Koch Institute through funds from the Federal Ministry of Health (Grant no. 1369-341). We wish to thank the families for providing serum samples for this study. We thank Viviane Grewe for providing technical assistance in organising the serum samples for this international collaboration, and the La Trobe University Statistics Consultancy Platform for statistical advice and analysis.

History

Publication Date

01/12/2021

Journal

Communications Biology

Volume

4

Issue

1

Article Number

ARTN 411

Pagination

12p.

Publisher

NATURE RESEARCH

ISSN

2399-3642

Rights Statement

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