Τίτλος:
Genome-wide transcriptomics identifies an early preclinical signature of prion infection
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The 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 and splicing alterations during the course of disease in prion-inoculated mice. Prion infection induced PrP-dependent 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 signs, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, could be the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed signs 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. © 2020 Sorce et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Συγγραφείς:
Sorce, S.
Nuvolone, M.
Russo, G.
Chincisan, A.
Heinzer, D.
Avar, M.
Pfammatter, M.
Schwarz, P.
Delic, M.
Müller, M.
Hornemann, S.
Sanoudou, D.
Scheckel, C.
Aguzzi, A.
Περιοδικό:
PLoS Pathogens
Εκδότης:
Public Library of Science
Λέξεις-κλειδιά:
adenosine; biological marker; clathrin; formic acid; immunoglobulin G1; inosine; ion channel; messenger RNA; nitrilotriacetic acid; penicillin G; prion protein; proteasome; proteinase K; RNA binding protein; RNA binding protein FUS; streptomycin; thioflavine; transcriptome; messenger RNA; transcriptome, adult; aged; animal experiment; animal model; animal tissue; Article; astrocyte; brain homogenate; cell adhesion; cohort analysis; controlled study; degenerative disease; enzyme linked immunospot assay; exon skipping; extracellular matrix; gene amplification; gene expression; gene ontology; genome-wide association study; gliosis; habituation; high throughput sequencing; hippocampus; immune response; immunoaffinity chromatography; immunohistochemistry; infection; male; microglia; mouse; neuroapoptosis; nonhuman; oligodendroglia; posttranscriptional gene silencing; preclinical study; principal component analysis; prion infection; real time polymerase chain reaction; real time quaking induced conversion assay; receptor down regulation; receptor upregulation; RNA editing; RNA sequencing; RNA splicing; rotarod test; synaptic transmission; transcardial perfusion; transcriptomics; young adult; animal; genetics; knockout mouse; metabolism; nerve cell; prion disease, Animals; Genome-Wide Association Study; Male; Mice; Mice, Knockout; Microglia; Neurons; Prion Diseases; RNA, Messenger; Transcriptome
DOI:
10.1371/journal.ppat.1008653
