Summary: A lipid anchor on nerve cell membranes stabilizes prion proteins (PrPC) and prevents their pathological aggregation into forms linked to prion diseases. Researchers developed new in vitro and cell models to study how membrane anchoring inhibits these harmful transformations.
They found that while anchoring stabilizes prion proteins, pre-formed aggregates can still induce clumping, suggesting a mechanism relevant to infectious prion diseases. These findings provide critical insights into protein misfolding and may inform therapeutic strategies for prion and other neurodegenerative diseases.
Key Facts:
- Lipid Anchors Role: Membrane anchors stabilize prion proteins, preventing pathological aggregation.
- Disease Mechanism: Pre-formed aggregates can induce clumping of anchored prion proteins, relevant to infectious prion diseases.
- Therapeutic Insight: Understanding protein stabilization could aid in developing treatments for prion and related diseases.
Source: RUB
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.”
Funding: The study was funded by the German Research Foundation: TA 167/6-3, WI/2111-6 and Cluster of Excellence Ruhr Explores Solvation (RESOLV, EXC 2033–390677874).
About this neurology and genetics research news
Author: Jörg Tatzelt
Source: RUB
Contact: Jörg Tatzelt – RUB
Image: The image is credited to AG Tatzelt
Original Research: Closed access.
“Topological Confinement by a Membrane Anchor Suppresses Phase Separation into Protein Aggregates: Implications for Prion Diseases” by Jörg Tatzelt et al. PNAS
Abstract
Topological Confinement by a Membrane Anchor Suppresses Phase Separation into Protein Aggregates: Implications for Prion Diseases
Protein misfolding and aggregation are a hallmark of various neurodegenerative disorders. However, the underlying mechanisms driving protein misfolding in the cellular context are incompletely understood.
Here, we show that the two-dimensional confinement imposed by a membrane anchor stabilizes the native protein conformation and suppresses liquid–liquid phase separation (LLPS) and protein aggregation.
Inherited prion diseases in humans and neurodegeneration in transgenic mice are linked to the expression of anchorless prion protein (PrP), suggesting that the C-terminal glycosylphosphatidylinositol (GPI) anchor of native PrP impedes spontaneous formation of neurotoxic and infectious PrP species.
Combining unique in vitro and in vivo approaches, we demonstrate that anchoring to membranes prevents LLPS and spontaneous aggregation of PrP. Upon release from the membrane, PrP undergoes a conformational transition to detergent-insoluble aggregates.
Our study demonstrates an essential role of the GPI anchor in preventing spontaneous misfolding of PrPC and provides a mechanistic basis for inherited prion diseases associated with anchorless PrP.
