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

PLoS Pathog. 2020 Jun 29;16(6):e1008653. doi: 10.1371/journal.ppat.1008653. eCollection 2020 Jun.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Genome-Wide Association Study*
  • Male
  • Mice
  • Mice, Knockout
  • Microglia / metabolism*
  • Neurons / metabolism*
  • Prion Diseases* / genetics
  • Prion Diseases* / metabolism
  • RNA, Messenger* / genetics
  • RNA, Messenger* / metabolism
  • Transcriptome*


  • RNA, Messenger

Grant support

A.A. is the recipient of an Advanced Grant of the European Research Council (670958), the Swiss National Foundation (179040, 183563), the Clinical Research Priority Programs “Small RNAs” and “Human Hemato-Lymphatic Diseases”, the Nomis Foundation and a donation from the estate of Dr. Hans Salvisberg. S.S. is recipient of a grant from the Synapsis foundation. M.N. is recipient of a grant from the Amyloidosis Foundation. C.S. was supported by a Marie Curie Individual Fellowship (706138). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.