Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation

Conformational conversion of the α-helix-rich cellular prion protein into the misfolded, β-rich, aggregated, scrapie form underlies the molecular basis of prion diseases that represent a class of invariably fatal, untreatable, and transmissible neurodegenerative diseases. However, despite the extensive and rigorous research, there is a significant gap in the understanding of molecular mechanisms that contribute to prion pathogenesis. In this review, we describe the historical perspective of the development of the prion concept and the current state of knowledge of prion biology including structural, molecular, and cellular aspects of the prion protein. We then summarize the putative functional role of the N-terminal intrinsically disordered segment of the prion protein. We next describe the ongoing efforts in elucidating the prion phase behavior and the emerging role of liquid-liquid phase separation that can have potential functional relevance and can offer an alternate non-canonical pathway involving conformational conversion into a disease-associated form. We also attempt to shed light on the evolutionary perspective of the prion protein highlighting the potential role of intrinsic disorder in prion protein biology and summarize a few important questions associated with the phase transitions of the prion protein. Delving deeper into these key aspects can pave the way for a detailed understanding of the critical molecular determinants of the prion phase transition and its relevance to physiology and neurodegenerative diseases.