How the Prion Protein Clumps

Researchers at the Federal University of Rio de Janeiro (UFRJ) have identified that the interaction between prion proteins and DNA may be behind both the formation of protein amyloid aggregates and the emergence of neurodegenerative diseases such as Creutzfeldt-Jakob disease and other spongiform encephalopathies. The study was published today in the FASEB Journal.

The scientists have found that the prion protein (PrP) suffers liquid–liquid phase separation and that this mechanism is finely controlled by some DNA sequences. In a process similar to oil droplets dispersed in an oil–water emulsion, the DNA leads PrP to form liquid droplets, putting it into a gel-like state or even changing it into a solid. The researchers have also observed that these properties depend on the conformation of the DNA aptamer (a hairpin or extended conformation) and on the stoichiometry of the protein–nucleic acid interaction.

The process of changing liquid droplets into a solid state could explain the formation of amyloid aggregates—the abnormal and irreversible clumping of the prion protein. These structures are toxic to the brain and are related to the development of transmissible spongiform encephalopathies, such as the Creutzfeldt-Jakob disease and the bovine spongiform encephalopathy (BSE), commonly known as mad cow disease. The link between amyloid aggregates and the diseases has been known for years, but how these structures form remains unclear. The new study brings insights that might help answer this question.

The study’s main finding is that the prion protein binds nucleic acids in a similar fashion to other well-described proteins that cause other neurodegenerative diseases. This finding opens the possibility of targeting the resulting diseases by selecting specific DNA sequences that could prevent the organelles from turning into non-functional gels and solids.

Image: The globular domain of the prion protein (PrP90-231), depicted in blue, binds different DNA aptamers that have different conformations (hairpin, red; extended, black). Upon binding to these DNA sequences, PrP phase separates, and, depending on the conformation of the nucleic acid, a solid-like structure is formed (green), similar to the one found in the brain of carriers of neurodegenerative diseases related to protein misfolding, such as amyotrophic lateral sclerosis and Parkinson's Disease. Image courtesy of Carolina Matos and Anderson Pinheiro.