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Updated: Dec 17, 2025
Assessing Transmissible Spongiform Encephalopathy Species Barriers with an In Vitro Prion Protein Conversion Assay
Published on: March 10, 2015
Genome-wide transcriptomics identifies an early preclinical signature of prion infection
Silvia Sorce1, Mario Nuvolone1,2, Giancarlo Russo3
1Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
Abstract:
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.
Insights
Prion diseases show early molecular changes in mRNA, preceding clinical signs. Glial changes, not neuronal, may drive disease progression, offering potential biomarkers and therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Genomics
Background:
- Prion diseases are fatal neurodegenerative disorders characterized by a long preclinical phase.
- The molecular events driving prion pathogenesis and disease progression remain incompletely understood.
- Predictable clinical courses suggest precisely timed molecular events underlie prion disease.
Purpose of the Study:
- To construct a genome-wide atlas of mRNA abundance and splicing alterations during prion disease progression in mice.
- To identify early molecular changes indicative of prion infection.
- To investigate the roles of glial and neuronal cells in disease pathogenesis.
Main Methods:
- Construction of a searchable genome-wide atlas of mRNA abundance and splicing.
- Analysis of molecular changes in prion-inoculated mice at various time points post-inoculation.
- Comparison of gene expression patterns in response to prion infection, focusing on glial and neuronal transcripts.
Main Results:
- Prion infection induced transient, PrP-dependent changes in mRNA abundance and processing as early as eight weeks post-inoculation, preceding clinical and neuropathological signs.
- Microglia-enriched genes increased concurrently with clinical signs, while neuronal transcripts remained unchanged until late-stage disease.
- Administration of young plasma attenuated early molecular alterations and delayed terminal disease signs.
Conclusions:
- Early molecular changes, including mRNA alterations, occur well before clinical manifestation of prion disease.
- Glial pathophysiology, rather than neuronal loss, may be the primary driver of terminal prion disease.
- Identified early molecular events represent potential biomarkers and therapeutic targets for prion diseases.
