부산대학교 도서관

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. Author summary: Prion diseases are brain disorders caused by infectious proteins called prions. These diseases feature a long asymptomatic incubation phase which can last several years, followed by a phase of rapidly progressing mental deterioration that can lead to death within just few months. The mechanisms underlying the long incubation phase are elusive, impeding early diagnosis and limiting potential therapeutic interventions. In experiments, prion-infected mice develop the disease following a timeline similar to that of human prion diseases. Here we have studied gene expression at different time points during the development of disease in mice. Our results indicate that robust molecular changes can be detected much earlier than previously anticipated, months before mice begin to show clinical signs or brain tissue damage. Several months later, a reaction of glial cells heralds the overt clinical manifestations of disease. Experimental treatment aimed at "rejuvenating" mice prevents the early molecular changes and seems to impact on the subsequent later disease progression. Although therapies for prion diseases are still lacking, our data redefine the disease stages from a molecular perspective and might contribute to devise better-timed and potentially more efficacious interventions. [ABSTRACT FROM AUTHOR]