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Groundbreaking discovery reveals key role of ATG5 in neuronal survival and brain health
In an exciting breakthrough, a team of researchers has unveiled a crucial mechanism by which autophagy, the body’s cellular recycling process, protects brain function by regulating glucose metabolism. The study, led by Professor Dr. Natalia Kononenko at the CECAD Cluster of Excellence for Aging Research, in collaboration with the University of Cologne, Forschungszentrum Jülich, and the University of Lausanne, was recently published in Nature Metabolism.
Autophagy, long known for its role in clearing damaged cellular components, has been shown to have a critical impact on neuroprotection. However, the precise mechanisms through which autophagy maintains brain health have remained largely unclear—until now.
The new study, titled “Autophagy Regulator ATG5 Preserves Cerebellar Function by Safeguarding its Glycolytic Activity,” demonstrates that autophagy, through a key player known as ATG5, helps preserve neuronal function by regulating glucose metabolism in the brain, specifically within Purkinje cells. These neurons, found in the cerebellum, are vital for motor coordination.
ATG5 plays a vital role in preventing the overaccumulation of glucose transporter 2 (GLUT2) on the surface of Purkinje cells. This regulation controls glycolysis—the process by which cells convert glucose into energy. By maintaining this balance, ATG5 prevents the buildup of toxic metabolic by-products that can result in cell death and neuronal dysfunction.
Using advanced techniques such as PET imaging, multi-omics, and 3D kinematics, the research team investigated mice lacking ATG5. The results were striking: without ATG5, GLUT2 accumulated excessively, leading to increased glucose uptake, disrupted glycolysis, and the production of harmful metabolic by-products. These disturbances ultimately caused Purkinje cell death, resulting in motor gait dysfunction.
“Our research demonstrates that autophagy isn’t just about clearing damaged mitochondria or protein aggregates,” explained Dr. Janine Tutas, the study’s first author. “In Purkinje cells, ATG5 actively regulates metabolic pathways to prevent cell death.”
Professor Dr. Kononenko emphasized the significance of these findings: “These results highlight the sophisticated ways autophagy supports neuronal health beyond its traditional roles.”
This groundbreaking discovery holds promise for understanding how the brain combats neurodegeneration. The research provides new insights into conditions such as Parkinson’s and Alzheimer’s diseases, where both metabolic and autophagic dysfunctions are often present. While this mechanism has been demonstrated in mice, further studies will aim to explore how autophagy regulates metabolism in both mice and human-based models of neurodegenerative diseases.
As the field of brain health advances, this study opens the door for potential new treatments for neurodegenerative disorders, potentially improving the lives of millions affected by these conditions.
For more information, refer to the original study: Tutas, J., et al. (2025). Autophagy Regulator ATG5 Preserves Cerebellar Function by Safeguarding its Glycolytic Activity. Nature Metabolism, DOI: 10.1038/s42255-024-01196-4.
