Summary: SUMO proteins play a key role in activating dormant neural stem cells, vital for brain repair and regeneration. This finding, centered on a process called SUMOylation, reveals how neural stem cells can be “woken up” to aid in brain recovery, offering potential treatments for neurodegenerative diseases.
SUMO proteins regulate neural stem cell reactivation by modifying the Hippo pathway, crucial for cell growth and repair. The study’s insights lay foundational groundwork for developing regenerative therapies to combat conditions like Alzheimer’s and Parkinson’s disease.
Key Facts:
- SUMO proteins activate dormant neural stem cells, aiding brain repair.
- SUMOylation regulates neural stem cells by modulating the Hippo pathway.
- Findings offer a basis for regenerative treatments for neurodegenerative diseases.
Source: Duke NUS Medical School
An international team of neuroscientists, led by Duke-NUS Medical School, have uncovered a mechanism that controls the reactivation of neural stem cells, which are crucial for repairing and regenerating brain cells.
The research, published in Nature Communications, offers exciting potential for advancing our understanding and treatment of common neurodegenerative diseases like Alzheimer’s and Parkinson’s disease.
Neural stem cells are the source of the brain’s primary functional cells. After the initial development of the brain, neural stem cells typically enter a dormant state, conserving energy and resources. They re-awaken only when the brain needs them, such as after an injury or with physical exercise.
However, with age, fewer neural stem cells can be roused from their dormant state, leading to various neurological conditions. Understanding how this reactivation is regulated is essential for developing treatments for various neurological conditions.
In this study, the team discovered that a specific group of proteins play an essential role in “waking up” dormant neural stem cells through a process called SUMOylation.
In SUMOylation, 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, the researchers found, trigger the reactivation of neural stem cells, allowing them to contribute to brain development and repair.
Conversely, without SUMO proteins present, the fruit flies produced a microcephaly-like phenotype. This is the first study to pinpoint the SUMO protein family’s exact role in the reactivation of neural stem cells.
Dr Gao Yang, a research fellow with Duke-NUS’ Neuroscience and Behavioural Disorders Programme and the study’s first author, remarked:
“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.”
Delving deeper into the effects of SUMOylation, the researchers determined that it regulates a key protein in another well-known pathway, called Hippo. While the Hippo pathway is known to play a crucial role in cellular processes such as cell proliferation, cell death and organ size, very few regulators of this pathway in the brain are known.
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. This allows neural stem cells to grow and divide, forming new neurons that contribute to brain function.
Professor Wang Hongyan, Acting Programme Director of the Neuroscience and Behavioural Disorders Research Programme and senior author of the study, said:
“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.”
Prof Wang and her team had previously demonstrated that fruit fly neural stem cells are an excellent model for unravelling the mysteries of dormancy, reactivation and neuronal regeneration.
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, commented:
“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.”
Duke-NUS is a leader in medical research and education, with a commitment to improving patient care through innovative scientific discovery.
This study is part of its ongoing efforts to deepen understanding of the fundamental mechanisms at play in the human brain to create new therapeutic approaches, especially for patients with neurological conditions.
About this genetics and neuroscience research news
Author: Brandon Raeburn
Source: Duke NUS Medical School
Contact: Brandon Raeburn – Duke NUS Medical School
Image: The image is credited to Neuroscience News
Original Research: Open access.
“SUMOylation of Warts Kinase Promotes Neural Stem Cell Reactivation” by Gao Yang et al. Nature Communications
Abstract
SUMOylation of Warts Kinase Promotes Neural Stem Cell Reactivation
A delicate balance between neural stem cell (NSC) quiescence and proliferation is important for adult neurogenesis and homeostasis.
Small ubiquitin-related modifier (SUMO)-dependent post-translational modifications cause rapid and reversible changes in protein functions. However, the role of the SUMO pathway during NSC reactivation and brain development is not established.
Here, we show that the key components of the SUMO pathway play an important role in NSC reactivation and brain development in Drosophila.
Depletion of SUMO/Smt3 or SUMO conjugating enzyme Ubc9 results in notable defects in NSC reactivation and brain development, while their overexpression leads to premature NSC reactivation.
Smt3 protein levels increase with NSC reactivation, which is promoted by the Ser/Thr kinase Akt. Warts/Lats, the core protein kinase of the Hippo pathway, can undergo SUMO- and Ubc9-dependent SUMOylation at Lys766.
This modification attenuates Wts phosphorylation by Hippo, leading to the inhibition of the Hippo pathway, and consequently, initiation of NSC reactivation. Moreover, inhibiting Hippo pathway effectively restores the NSC reactivation defects induced by SUMO pathway inhibition.
Overall, our study uncovered an important role for the SUMO-Hippo pathway during Drosophila NSC reactivation and brain development.
