Repetitive RNA Is Present in Prion-Infected Mouse Brains

Abstract

Scrapie, a prion disease, is usually considered a protein-only infection. However, the repetitive nature of the protein-containing fibrils of prion disease and other neurodegenerations, including Alzheimer’s and Parkinson’s diseases, has led to the hypothesis that RNA, specifically a repetitive RNA, may be present [1–3]. A publicly available RNA-seq dataset from a previous study of mice infected with scrapie [4], was repurposed to test this hypothesis. Using the software superSTR [5], for detecting repetitive elements in RNA-seq data, repeat expansions were found for the known pathogenic motifs, AGC and AAG, along with other motifs, AAAAC, AAAGG, AAGAG and AGAU, all statistically significant compared to controls, with the Mann-Whitney U-test adjusted for multiple testing. They were present at both early and late time points in the disease. Using AlphaFold 3 [6], single- and double-stranded helical structures were predicted for these repetitive RNAs, with the potential to dysregulate protein translation [7] and trigger an interferon type 1 response [8]. Furthermore, the repetitive RNAs were predicted to bind to the prion protein, PrP. The present results suggest a two-component prion, a combined proteinopathy and RNAopathy, with dual toxicity, and raise the possibility of future new diagnostic tests and treatments for prion disease and other neurodegenerations.