Abstract
Recent studies have proposed that nucleic acids act as potential cofactors for protein aggregation and prionogenesis. By means of sedimentation, transmission electron microscopy, circular dichroism, static and dynamic light scattering, we have studied how RNA can influence the aggregation of the murine recombinant prion protein (rPrP). We find that RNA, independent of its sequence, source and size, modulates rPrP aggregation in a bimodal fashion, affecting both the extent and the rate of rPrP aggregation in a concentration dependent manner. Analogous to RNA-induced liquid-liquid phase transitions observed for other proteins implicated in neurodegenerative diseases, high protein to RNA ratios stimulate rPrP aggregation, while low ratios suppress it. However, the latter scenario also promotes formation of soluble oligomeric aggregates capable of seeding de novo rPrP aggregation. Furthermore, RNA co-aggregates with rPrP and thereby gains partial protection from RNase digestion. Our results also indicate that rPrP interacts with the RNAs with its N-terminus. In summary, this study elucidates the proposed adjuvant role of RNA in prion protein aggregation and propagation, and thus advocates an auxiliary role of the nucleic acids in protein aggregation in general.
Highlights
Prion diseases such as Transmissible Spongiform Encephalopathies (TSE) are a group of infectious disorders, which irreversibly cripple the nervous system of humans and other mammals[1,2]
We investigate the role of RNA in the aggregation of the full-length, recombinant, murine prion proteins (PrP) by using static light scattering (LS), dynamic light scattering (DLS), sedimentation, transmission electron microscopy (TEM) and circular dichroism (CD)
Our results suggest a modulatory role of RNA in recombinant prion protein (rPrP) aggregation, where high protein to RNA ratios lead to the formation of large amorphous aggregates of rPrP, whereas low ratios prevent it, and in turn, generate soluble, oligomeric species that can seed de novo rPrP aggregation
Summary
Prion diseases such as Transmissible Spongiform Encephalopathies (TSE) are a group of infectious disorders, which irreversibly cripple the nervous system of humans and other mammals[1,2]. Apart from demonstrating that nucleic acids could facilitate prion conversion[27,28,29,30,31,32,33,34,35], we recently reported that DNA and RNA modulate the aggregation of the tumor suppressor protein p5335–38. Maharana et al.[25] show that high protein to RNA ratios promote phase separation and aggregation of the prion-like RNA binding proteins such as TDP43 and FUS, whereas low ratios prevent it In accordance with these findings, the emerging concept is that the amyloid fibrils arise from more dynamic liquid droplets and glassy-solid states[48,49], where RNA acts as phase modulator[26,35,39,50]. We propose that RNA is an active player in rPrP aggregation, capable of modulating the outcome by direct interaction
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
