Ferroptosis Drives Brain Cell Death in Prion Diseases
Researchers led by Dr. Joel Schick at Helmholtz Munich, in collaboration with Dr. Cathryn Haigh from the National Institutes of Health (NIH), have identified a key mechanism driving brain cell death in prion diseases – a group of rare but fatal neurodegenerative conditions, including Creutzfeldt-Jakob Disease (CJD). Their findings highlight ferroptosis – an iron-dependent form of cell death characterized by oxidative stress and lipid peroxidation – as a central mechanism of disease progression.
What Are Prion Diseases?
Prion diseases are caused by the accumulation of misfolded brain proteins known as prions, which trigger a cascade of abnormal folding in surrounding proteins. This chain reaction causes severe brain damage, memory loss, and rapidly progressing dementia. These conditions are currently incurable and uniformly fatal.
Ferroptosis: A Key Mechanism of Neuronal Damage
At the heart of the new finding is ferroptosis, a regulated form of cell death driven by iron overload, oxidative stress, and damage to cell membranes through lipid peroxidation. The study shows that endogenous and misfolded prion proteins create the cellular conditions that promote ferroptosis, particularly in neurons.
The discovery builds on earlier work by the team, which identified the Fatty Acid-Binding Protein 5 (FABP5) as a biomarker and contributor to ferroptosis in brain tissue. The team now demonstrates the prion protein’s role in creating a cellular environment conducive to ferroptosis by altering oxidative stress levels and lipid composition, revealing a previously unknown pathway of disease progression.
RAC3: A Missing Piece in the Puzzle
The study newly highlights the importance of RAC3, a protein that facilitates ferroptosis. Cells expressing RAC3 were substantially lost in brain regions affected by prion buildup, a decrease directly correlated with the severity of neuronal damage.
“RAC3 seems to play a facilitative role,” says corresponding author Joel Schick. “Its presence contributes to ferroptosis being triggered. This makes it a very compelling candidate for future therapeutic targeting.”
Towards New Treatment Strategies
Although this study focuses on CJD, its findings may extend to other prion-related disorders that share similar pathogenic mechanisms, such as mad cow disease. As ferroptosis gains recognition as a key player in various neurodegenerative diseases, deeper insights into its regulation in prion diseases could pave the way for novel therapeutic approaches.
“This study enhances our understanding of shared pathways in neurodegeneration,” explains Schick. “By targeting ferroptosis and key regulators like RAC3, we hope to open new avenues for treatment – not only for CJD but potentially for a broader spectrum of prion-related conditions.“
Original Publication
Peng at al. 2025: Prion-induced ferroptosis is facilitated by RAC3. Nature Communications. DOI: 10.1038/s41467-025-60793-3
About the scientist
Dr. Joel Schick leads the Genetics and Cellular Engineering Group at the Molecular Targets and Therapeutics Center at Helmholtz Munich.
Funding information
This work was primarily supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under project number 501860452.
Dr. Borys Varynskyi, a co-author of the study, has recently received funding support from the Philipp Schwartz Initiative of the Alexander von Humboldt Foundation and will continue his research in the group of Dr. Joel Schick at Helmholtz Munich.
The Philipp Schwartz Initiative was launched in 2015 by the Alexander von Humboldt Foundation and the Federal Foreign Office of Germany. It provides funding for researchers who are exposed to significant and ongoing risks in their home countries, enabling them to continue their scientific work at academic institutions in Germany.
Joel Schick | Nature Communications
