The "Jekyll and Hyde" Actions of Nucleic Acids on the Prion-like Aggregation of Proteins

Abstract

Protein misfolding results in devastating degenerative diseases and cancer. Among the culprits involved in these illnesses are prions and prion-like proteins, which can propagate by converting normal proteins to the wrong conformation. For spongiform encephalopathies, a real prion can be transmitted among individuals. In other disorders, the bona fide prion characteristics are still under investigation. Besides inducing misfolding of native proteins, prions bind nucleic acids and other polyanions. Here, we discuss how nucleic acid binding might influence protein misfolding for both disease-related and benign, functional prions and why the line between bad and good amyloids might be more subtle than previously thought.

Keywords: cancer; functional amyloid; functional amyloids; neurodegenerative disease; nucleic acid; p53; prion; prions; protein aggregation; protein misfolding.

FIGURE 1.

Free energy diagram representing the role of polyanions in the conversion reaction from PrP^C to PrP^Sc. DNA, RNA, phospholipid (PL), and glycosaminoglycan (GAG) molecules may bind PrP^C and lower the energy barrier that prevents its conversion to the pathogenic, misfolded form, PrP^Sc. PrP^C binding to different cofactor molecules may change the efficiency of the conversion to PrP^Sc and/or result in the generation of PrP^Sc with varying conformations (i.e. prion strains, depending on the nature of the cofactor). Modified from Refs. and .

FIGURE 2.

Cellular representation of functional (blue, right) and misfunctional (red, left) interactions of proteins involved in neurodegenerative disorders with nucleic acids. Three RNA-binding proteins were selected as examples: PrP, FUS/TLS, and TDP-43. FUS/TLS and TDP-43 have RRMs and glycine-rich, prion-like domains. Both FUS-TLS and TDP-43 are found to be functional in the nucleus, where they bind RNA and can associate to form stress granules with RNA and other proteins (physiological stress response). Mutations in TDP-43 and FUS/TLS can cause ALS and FTLD that relate to dysfunction or dysregulation of neuronal RNA granules and SGs in the cytoplasm. It is hypothesized that the prolonged presence of aggregated TDP-43 (mutation, aging) in the cytoplasm contributes to degeneration by interfering with mRNA homeostasis (pathological stress granules). Besides, both native and mutant FUS/TLS can form reversible (blue, right) and irreversible (red, left) hydrogels, respectively, that trap RNA-binding proteins and RNA. PrP is in general found anchored to the cell membrane (upper right side), but it also interacts with nucleic acids (both DNA and RNA) with a yet unknown function. It aggregates upon interaction with RNA, and these aggregates can be toxic to cells. RGG, Arg-Gly-Gly repeat.

FIGURE 3.

Free energy landscape showing native, misfolded, amyloid oligomers and fibrils of p53 along the folding funnel. Aggregation of mutant p53 is an important therapeutic target. Researchers have been trying to use peptides, aptameric nucleic acids, and small molecules (SMs) to prevent the formation of aggregates, responsible for the dominant-negative effects and gain-of-function effects of mutant p53. Modified from Refs. and .