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

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.

Gene expression and epigenetic markers of prion diseases

“…Higher levels of four of these transcripts were found in sCJD in comparison to blood from controls, which is consistent with a reduction of miRNA silencing of target mRNA. In mice, Cheng and colleagues demonstrated dynamic expression changes during disease progression in the affected thalamus region and serum (Cheng et al 2021 ). The authors validated these differentially expressed miRNAs in extracellular vesicles from human blood samples from patients with sCJD and controls and found that a diagnostic model using miRNA biomarkers associated with prion infection (predicting sCJD with an AUC of 0.800, 85% sensitivity, and 66.7% specificity).…”

Bioinformatics and System Biology Techniques to Determine Biomolecular Signatures and Pathways of Prion Disorder

“…75 Another miRNA, hsa-mir-148b-3p, has been linked to PD and could potentially be employed as a biomarker for PD. 76 In addition to transcriptome expression, epigenome controls and mutations can have an impact on PD. From the foregoing explanation, we can deduce that the pathophysiology of this psychiatric condition is influenced by genetic, transcriptomic, posttranscriptomic, and epigenetic patterns at the architectural level.…”

“… 75 Another miRNA, hsa-mir-148b-3p, has been linked to PD and could potentially be employed as a biomarker for PD. 76 …”

Extracellular vesicles with diagnostic and therapeutic potential for prion diseases

“…Further evidence of brain EVs detected in the blood includes EVs isolated from blood samples of mice that have received human glioma transplants (García-Romero et al 2017 ). In addition, brain tissue–derived EV isolation can enhance the precision of diagnosis related to the affected region when correlated together with the blood-based differential miRNAs and proteins in EVs for biomarker discovery (Cheng et al 2021 ).…”