Abstract
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.
Highlights
Prion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration
A previously established in vivo model of prion disease with the M1000 prion strain was employed in this study[3,11]
In order to investigate temporal-specific differences in expression accompanying disease progression, we examined all miRNA transcripts that were present in the thalamus over the course of prion infection using next-generation sequencing
Summary
Prion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration. To investigate the temporal miRNA expression patterns in a specific brain region, we have utilised a well-characterised in vivo mouse model with the M1000 prion strain that is a mouseadapted human strain isolated from a patient who died from GSS11,12. These infected mice develop first signs of neuropathology after the mid-incubation period, weeks postinoculation (wpi), in the thalamus and hippocampus which spreads to the occipital cortex and brain stem from wpi with M1000-prions[3]. Those who are V homozygous have been observed to have a clinical duration of 3–18 months where the mean age of onset to be between 41 and 81 years (reviewed in ref. 14)
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