Membrane Anchor Suppresses Protein Aggregation
Researchers have gained valuable insight into the development of prion diseases of the brain
Protein aggregation is typical of various neurodegenerative diseases such as Alzheimer’s, Parkinson’s and prion diseases such as Creutzfeld-Jakob disease. A research team headed by Professor Jörg Tatzelt from the Department of Biochemistry of Neurodegenerative Diseases at Ruhr University Bochum, Germany, has now used new in vitro and cell culture models to show that a lipid anchor on the outer membrane of nerve cells inhibits the aggregation of the prion protein. “Understanding the mechanisms that cause the originally folded proteins to transform into pathogenic forms is of crucial importance for the development of therapeutic strategies,” says Jörg Tatzelt. The team published their findings in the journal Proceedings of the National Academy of Sciences (PNAS) on December, 31, 2024.
Hereditary and infectious forms of the disease
Prion diseases are fatal degenerative diseases of the brain. They are associated with the transformation of the cellular prion protein (PrPC) from its healthy fold into pathological aggregates, i.e. scrapie prion protein (PrPSc). While such diseases are rare in humans, hereditary prion diseases are triggered by genetic mutations. Some gene mutations affect the anchoring of PrPC to the cell membrane. However, it is still not fully understood exactly how these changes can trigger prion diseases.
In order to gain new insights into the underlying processes, the researchers have developed new models to explore the role of a membrane anchor on the folding and aggregation of PrP in vitro and in neuronal cells. The experiments showed that anchoring to membranes stabilizes the folding of PrP and effectively inhibits aggregation. “What’s interesting is that the clumping of membrane-anchored PrP could be induced by pre-formed protein aggregates,” says Jörg Tatzelt. “This is a mechanism that might play a role in infectious prion diseases.”
Original publication
Kalpshree Gogte, Fatemeh Mamashli, Maria Georgina Herrera, Simon Kriegler, Verian Bader, Janine Kamps, Prerna Grover, Roland Winter, Konstanze F. Winklhofer, Jörg Tatzelt; "Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases"; Proceedings of the National Academy of Sciences, Volume 122, 2024-12-31
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