Protein aggregation is a common characteristic of various neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and prion diseases like Creutzfeldt-Jakob disease. A team of researchers has now utilized innovative in vitro and cell culture models to demonstrate that a lipid anchor located on the outer membrane of nerve cells can prevent the prion protein from aggregating.
Researchers have made significant advancements in understanding the development of prion diseases in the brain.
Protein aggregation is a hallmark of multiple neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, alongside prion diseases including Creutzfeldt-Jakob disease. The research team led by Professor Jörg Tatzelt from the Department of Biochemistry of Neurodegenerative Diseases at Ruhr University Bochum, Germany, has recently employed novel in vitro and cell culture models. They found that a lipid anchor on the outer membrane of nerve cells serves to inhibit the aggregation of prion protein. “It is vital to understand how properly folded proteins convert into pathogenic forms to create effective therapeutic approaches,” explains Jörg Tatzelt. The team shared their discoveries in the journal Proceedings of the National Academy of Sciences (PNAS) on December 31, 2024.
Genetic and infectious variants of the disease
Prion diseases are lethal degenerative conditions impacting the brain, marked by the conversion of the normal cellular prion protein (PrPC) into harmful aggregates known as scrapie prion protein (PrPSc). Although these diseases are uncommon in humans, genetic mutations can lead to hereditary prion diseases. Certain mutations affect how PrPC is anchored to the cell membrane. However, the precise mechanisms by which these mutations induce prion diseases remain unclear.
To shed light on these processes, the researchers developed new models to investigate the impact of a membrane anchor on the folding and aggregation of PrP both in vitro and within neuronal cells. Their findings revealed that membrane anchoring enhances the stability of PrP folding and effectively reduces aggregation. “Interestingly, the clustering of membrane-anchored PrP could be triggered by pre-formed protein aggregates,” notes Jörg Tatzelt. “This mechanism could have implications for the understanding of infectious prion diseases.”
