In a breakthrough discovery, neuroscientists from Duke-NUS Medical School and the National University of Singapore have found a way to reactivate latent neural stem cells. This could potentially facilitate brain repair and regeneration for new treatments in neurodevelopment and degenerative disorders such as cerebral palsy, autism, and Alzheimer’s disease.
Dormant Neural Stem Cells: Sleeping Giants of Brain Repair
Neural stem cells reside in specific regions of the brain and have the critical role of contributing to brain development and repair by giving rise to new neurons. However, in adults, these cells are usually quiescent until they receive specific signals that “wake them.” The challenge has been to understand the exact mechanisms that may trigger this reactivation, since defects in these processes are linked with cognitive decline in aging and a variety of neurodevelopmental disorders.
The team concentrated on the fruit fly because the neural stem cells in the flies have many similarities to those in mammals. Using these models, the scientists found that glial cells, including astrocytes, produce a critical signaling protein called Folded Gastrulation, or Fog. This kicked off a chain reaction that ultimately reactivated these quiescent neural stem cells. Once reactivated, the cells can make new neurons, enabling the repair and growth of brains.
The Role of Astrocytes in Brain Cell Activation
Astrocytes have long been thought to be purely support cells; however, this understanding of their function in the health of the brain was unexpected—their use in releasing Fog and interacting with the GPCR receptor protein in neural stem cells being the major revelation. This pathway directly affects the polymerization of actin filaments in neural stem cells, which is one of the necessary steps for awakening quiescent neural stem cells. The identification of this pathway is important because it provides new options for therapeutic treatments.
This discovery in the context of the already repurposing of FDA-approved drugs targeting the GPCR protein family suggests a potential in repurposing existing medications to influence neural stem cell activation for new treatments of such disorders as autism and cerebral palsy.
Clinical Implications: Neurological Disorders Get Hope
These findings have particular promise for neurodevelopmental disorders, which affect perhaps 5% of all children and adolescents worldwide, often with impairments in cognitive and motor functions. It is possible that some of these impairments could be counteracted, or even reversed, by reactivating quiescent neural stem cells.
Neurodegenerative consequences beyond neurodevelopmental disorders include conditions such as Alzheimer’s and Parkinson’s disease. It has been hoped that the reactivation of such neural stem cells would enhance repair mechanisms in the brain and thereby slow disease processes. Such therapies promise significant enhancements in the quality of life for aging populations in whom cognitive decline has become so common.
New Frontiers: The SUMOylation Pathway
Another investigation published in *Nature Communications focused on a different molecular process known as SUMOylation, which controls the activity of proteins responsible for controlling NSC activation. In this process, the covalent attachment of the small ubiquitin-like modifier SUMO to certain proteins modulates the activity of key signaling pathways, including the Hippo pathway, which is important for the control of cell proliferation and organ size. Disruption of this process leads to microcephaly, a condition that involves an abnormally small brain.
SUMOylation is a critical regulator of the division and proliferation potential of neural stem cells and may thus serve to balance the neurodegenerative effects. The possibility of manipulating this pathway offers another direction in the development of therapies aimed at the reactivation of latent NSCs in support of brain health in a variety of disorders.
Looking Ahead: Future Research and Treatment Possibilities
The discovery that neuroscientists made in 2024 opened a new direction in studies. Further studies are likely to establish whether these mechanisms exist in humans and how they may be manipulated to treat neurological conditions. Besides, the involvement of astrocytes in the development of the brain and response to injury is better understood; implications of these findings are expected to lead to a significant step forward in drug development.
Moreover, since diet and exercise are already recognized modifiable lifestyle factors influencing neurogenesis and cognition, there is interest in whether such mechanisms may also be subject to their regulation. The full range of signals, including those reviewed here, will be important for design of broadly effective treatments.
Finally, the reactivation of quiescent neural stem cells will represent an unprecedented paradigm shift in the way experts understand brain health. This line of investigation thus promises not only to improve our understanding of brain development but also to bring hope to millions of people all over the world who have neurodevelopment and neurodegenerative disorders.
