Genome-wide transcriptomics identifies an early preclinical signature of prion infection

Abstract

2The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance, splicing and editing alterations during the course of disease in prion-inoculated mice. Prion infection induced transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs. In contrast, microglia-enriched genes displayed an increase simultaneous with the appearance of clinical symptoms, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, represents the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed symptoms in the terminal phase of the disease. The early onset of prion-induced molecular changes might thus point to novel biomarkers and potential interventional targets. MainAfter the onset of clinical signs, prion diseases typically progress very rapidly to a terminal stage, which is characterized by micro-and astrogliosis, vacuolation and neuronal loss. Sporadic Creutzfeldt-Jakob disease (CJD), the most common human prion disease, can lead to death within months of symptom onset 1 .Conversely, prion infections are often characterized by very long incubation times: iatrogenic cases of CJD after administration of prion-contaminated growth hormone display incubation times of >20 years 2 and Kuru, an acquired form of prion disease, was reported to arise decades after consumption of contaminated materials 3 . The extraordinary duration of the latency phase has led to the presumption that CJD may be caused by a "slow virus". Although this hypothesis was dismissed 4 , prion pathogenesis is initially insidious and only acquires a rapid rate of progression in the late stages of disease.The seemingly incongruous combination of a very long latency and a rapidly progressing clinical disease can be reproduced in mouse models of prion infection 5 . After inoculation of prion-containing brain homogenate, wild-type mice experience an incubation period of several months followed by rapidly progressive neurological dysfunction. It was suggested that prion replication occurs without causing any neuronal damage until a plateau level of infectious particles is reached, whereas neurotoxicity arises because of a toxic form of PrP named "PrP L " 6-8 . However, no physical evidence for the existence of "PrP L " has ever come forth, and these experimental observations can be explained by alternative models. For example, small numbers of prion seeds may cause early molecular alterations that elicit late-onset clinical signs. This question may be addressed by File 3). Consistent with the hierarchical clustering and the PCA, 813 genes changed at 8 wpi and the number of DEGs gradually increased during the later timepoin...

Prion protein lowering is a disease-modifying therapy across prion disease stages, strains, and endpoints

“…In contrast, rotarod impairment became nominally detectable at 120 dpi, observable symptom profiles emerged by 116-135 dpi, and weight loss did not become obvious until 148 dpi. This is consistent with previous reports indicating neuroinflammatory changes can be observed by ~55-60 dpi 59,61,66 , neuronal damage between 60-75 dpi 67 , and behavioral or motor changes by ~105 dpi or later 66,68 .…”

“…Our study has important limitations. While we investigated two biomarkers and a large battery of symptom endpoints, our understanding of the natural history of experimental prion disease is by no means exhaustive, and other approaches have nominated putative pathological and symptomatic changes somewhat earlier than we observed here 59,66,68 . While we consistently observed an overall survival benefit to PrP-lowering therapy across nearly all paradigms tested, sometimes only a subset of mice benefitted, and the magnitude of therapeutic benefit observed sometimes varied between nearly identical experiments.…”

Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice

“…Library preparation, RNA sequencing and bioinformatic analysis were performed at the Functional Genomics Center Zurich (FGCZ). For sciatic nerves of untreated 4 months old mice and tibialis muscle of PrP overexpressing mice, library preparation and RNA sequencing were performed as described previously (Sorce et al, 2020). For mice in the chronic treatment experiment and 13-15 months untreated old mice, libraries were prepared using the TruSeq RNA stranded Library Prep Kit (Illumina, lnc) and sequencing was performed on the Illumina Novaseq 6000 instrument for single-end 100 bp reads.…”

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

“…The microglia are the resident macrophages of the CNS, and a change in their status from resting to activated is one of the earliest neuropathological features in the brain during prion disease, and occurs before the development of the neuropathology [ 146 , 147 , 148 ]. The microglia are established by embryonic day 8 in the brain from yolk sac-derived progenitors, and are mostly maintained by self-renewal in a CSF1R-dependent manner [ 149 , 150 ].…”