(Dys)functional insights into nucleic acids and RNA-binding proteins modulation of the prion protein and α-synuclein phase separation

• Published in: Biophysical reviews Vol. 15; no. 4; pp. 577 - 589
• Main Authors: Cordeiro, Yraima, Freire, Maria Heloisa O., Wiecikowski, Adalgisa Felippe, do Amaral, Mariana Juliani
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-08-2023; Springer Nature B.V
• Subjects: Binding; Biochemistry; Biological and Medical Physics; Biological Techniques; Biomedical and Life Sciences; Biophysics; Cell Biology; Infectious diseases; Life Sciences; Membrane Biology; Modulation; Movement disorders; Nanotechnology; Neurodegenerative diseases; Neurotoxicity; Nucleic acids; Parkinson's disease; Phase separation; Phase transitions; Polyanions; Polyelectrolytes; Prion protein; Proteins; Review; Ribonucleic acid; RNA; RNA-binding protein; Synuclein; Therapeutic targets; Aggregation; RNA-binding proteins; Nucleic acids; Prion protein; Phase separation; α-synuclein
• ISSN: 1867-2450; 1867-2469
• DOI: 10.1007/s12551-023-01067-4

Prion diseases are prototype of infectious diseases transmitted by a protein, the prion protein (PrP), and are still not understandable at the molecular level. Heterogenous species of aggregated PrP can be generated from its monomer. α-synuclein (αSyn), related to Parkinson’s disease, has also shown a prion-like pathogenic character, and likewise PrP interacts with nucleic acids (NAs), which in turn modulate their aggregation. Recently, our group and others have characterized that NAs and/or RNA-binding proteins (RBPs) modulate recombinant PrP and/or αSyn condensates formation, and uncontrolled condensation might precede pathological aggregation. Tackling abnormal phase separation of neurodegenerative disease-related proteins has been proposed as a promising therapeutic target. Therefore, understanding the mechanism by which polyanions, like NAs, modulate phase transitions intracellularly, is key to assess their role on toxicity promotion and neuronal death. Herein we discuss data on the nucleic acids binding properties and phase separation ability of PrP and αSyn with a special focus on their modulation by NAs and RBPs. Furthermore, we provide insights into condensation of PrP and/or αSyn in the light of non-trivial subcellular locations such as the nuclear and cytosolic environments.