A mechanism has been uncovered by an international team of neuroscientists led by Duke-NUS Medical Scheel that controls the reactivation of neural stem cells that are critical for repairing and regenerating brain cells. Their findings published in Nature Communications demonstrate the potential for advancing both understanding and treatment of common neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.
The brain’s primary functional cells are neural stem cells, and after initial development, they typically enter a dormant state to conserve energy and resources. However, they will re-awaken when the brain requires them, for example after an injury or with physical exercise. Unfortunately, as we age fewer of these neural stem cells can be aroused from their dormant state leading to various neurological conditions.
Investigating neural stem cells
Gaining a better understanding of how this reactivation is regulated could be important for the development of treatments for a range of neurological conditions. This study hopes to fill in some of those gaps, showing for the first time that modifying a protein that controls cell growth can reactivate these dormant neural stem cells in fruit flies through a process called SUMOylation, offering new hope in the fight against neurological diseases.
During the SUMOylation process, a small protein named SUMO (small ubiquitin-like modifier) tags target proteins inside a cell to influence their activity and/or function. These SUMO-tagged proteins were found to trigger the reactivation of neural stem cells, allowing them to contribute to brain development and repair. On the other hand, without these SUMO proteins present, the fruit flies produced a microcephaly-like phenotype. This is thought to be the first study to pinpoint the SUMO protein family’s exact role in the reactivation of neural stem cells.
“We have demonstrated for the first time that the SUMO protein family plays a pivotal role in neural stem cell reactivation and overall brain development. Going a step further, we also showed that when these proteins are absent, normal neuronal development is hampered, with fruit flies developing undersized brains characteristic of microcephaly,” said the study’s first author Dr Gao Yang, a research fellow with Duke-NUS’ Neuroscience and Behavioural Disorders Programme.
Delving deeper into the effects of SUMOylation
Further investigation into the effects of SUMOylation determined that it regulates a key protein in another well-known pathway, called Hippo. The Hippo pathway is known to play a critical role in cellular processes such as cell proliferation, cell death and organ size, but very few regulators of this pathway in the brain are known.
According to the researchers, when modified by SUMO, the Hippo pathway’s central protein Warts, which limits cell growth and prevents the reactivation of neural stem cells, becomes less effective and allows neural stem cells to grow and divide, forming new neurons that contribute to brain function.
Exciting new opportunities
“Given that SUMO proteins and the Hippo pathway are highly conserved in humans, our findings aren’t just relevant for fruit flies. They’re also important for understanding human biology. Disruptions in the SUMOylation process and Hippo pathway are linked to various illnesses in humans, including cancer and neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease. Our new insights into the role of SUMOylation in the brain opens exciting new opportunities for interventions that could lead to targeted therapies that harness the body’s own regenerative powers,” said senior author Professor Wang Hongyan, Acting Programme Director of the Neuroscience and Behavioural Disorders Research Programme.
“This discovery advances our understanding of how cells work and are controlled, informing the development of new regenerative therapeutics for neurodegenerative diseases. At the same time, it opens new possibilities for developing treatments for neurological conditions such as microcephaly. As research continues, we move closer to finding effective ways to help people with these disorders and improve their quality of life,” said Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS.
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References/Sources/Materials provided by:
https://www.nature.com/articles/s41467-024-52569-y
https://www.duke-nus.edu.sg/newshub/media-releases/SUMOylation
