Key Questions Answered:
Q: When do genes linked to mental illness begin to affect the brain?
Many genes associated with neuropsychiatric and neurodegenerative diseases are activated during the early stages of fetal brain development, much earlier than previously thought.
Question: How did researchers discover this early genetic activity?
By simulating the effects of nearly 3,000 disease-related genes on embryonic brain stem cells using data from human and mouse brains and in vitro models, the researchers were able to identify when and where these genes affect the brain development process.
Q: Why is this discovery important for treatment?
Understanding which genes act on specific cell types and developmental stages could lead to more precise and personalized treatments that target the underlying causes of mental and neurological disorders.
Summary: A major study has revealed that genes linked to brain and neurodegenerative disorders such as autism, depression and Parkinson’s disease affect brain development from the earliest stages of fetal development. These genes are active in neural stem cells (brain precursor cells) long before symptoms appear.
By combining data from humans and mice with laboratory-grown cell models, the researchers mapped the behavior of these genes across different developmental stages and brain cell types. This opens up new possibilities for early diagnosis, gene therapy, and targeted treatment of conditions previously thought to develop later in life.
Important facts:
- Primary source: Key disease-related genes are active in embryonic neural stem cells.
- Wide range of diseases: Genes linked to autism, schizophrenia, Alzheimer’s and other conditions become activated early.
- Treatment potential: The results could guide early interventions and gene-targeted therapies.
Source: IMIM
The origins of some neuropsychiatric disorders, such as autism, bipolar disorder and depression, and certain neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, can be traced to the early stages of fetal brain development.
This is earlier than previously thought, according to a study from the Hospital Del Mar Research Institute and Yale University, published in Nature Communications.
The aim of this work is to “discover the origins of brain diseases in the early stages of embryonic development, specifically in brain stem cells,” explains Dr. Gabriel Santperi, Miguel Servet researcher and coordinator of the Neurogenomics Research Group of the Biomedical Informatics Research Program at the Hospital del Mar Research Institute, a joint group with the University of Pobra Fabra.
To do this, they used a list of nearly 3,000 genes that are associated with neuropsychiatric disorders, neurodegenerative pathologies, and cortical dysfunction. They then simulated the effect of these changes on cells involved in brain development.
The results suggest that many of these genes are already at work during the early stages of embryonic development in stem cells, the precursor cells that build the brain and form neurons and their supporting structures.
This was no easy task. This stage of brain development is very difficult to study. So, the researchers combined various data from human and mouse brains, as well as in vitro cell models.
As Dr. Nicola Micali, a researcher in Dr. Pasko Rakic’s lab at Yale University and co-leader of this study, notes, “Scientists typically study genes for mental health disorders in adults, but in this study, we found that many of these genes are active in the early stages of fetal brain development, and these disrupt brain development and affect mental health later in life.”
During the study, specific regulatory networks for each cell type involved in brain development were simulated to observe how the analyzed genes, which are associated with various brain diseases, activate or deactivate progenitor cells at different stages. This made it possible to observe the importance of each gene in the development of changes that cause different diseases.
This list includes microcephaly and hydrocephalus, autism, depression, bipolar disorder, anorexia, and schizophrenia. Alzheimer’s and Parkinson’s diseases are also included.
All of these pathologies involve genes involved in the early stages of brain development, when neural stem cells function.
“We analyze how neural stem cells express genes associated with various brain conditions across a wide spectrum of disease types,” says Xoel Mato-Blanco, a researcher at the Hospital del Mar Research Institute.
At the same time, he notes that the work “identifies the time windows and cell types where the action of these genes is most relevant, suggesting when and where the function of these genes should be addressed.”
According to Dr. Saint-Pierre, this information is “useful for understanding the origins of diseases affecting the cerebral cortex, that is, how genetic changes give rise to these pathologies.”
Understanding these mechanisms and the role of each gene in each disease could help develop targeted therapies that target these mechanisms. This opens up the possibilities of gene therapy and personalized medicine.
About this genetics, mental health, and neurodevelopment research news
Author: Marta Calsina
Source: IMIM
Contact: Marta Calsina – IMIM
Image: The image is credited to StackZone Neuro
Original Research: Open access.
“Early developmental origins of cortical disorders modeled in human neural stem cells” by Gabriel Santpere et al. Nature Communications
Abstract
The early development of cortical disorders has been traced back to human neural stem cells.
The implications of early stages of human telencephalic development involving neural stem cells (NSCs) for the etiology of cortical disorders are still unclear.
Here we investigate the expression dynamics of genes associated with cortical and neuropsychiatric disorders in datasets generated from human neural stem cells with telencephalic fate transition in vitro and in vivo.
We have identified risk genes expressed in brain regulators and sequential gene regulatory networks during corticogenesis. This has revealed specific critical stages of disease, during which neural stem cells may be most vulnerable to genetic aberrations and aberrant signaling in multiple diseases.
Furthermore, we simulated the effects of reduction in risk transcription factors (TF) on the speed of neuronal cells undergoing corticogenesis in humans and observed a spatiotemporal dependent effect for each perturbation.
Finally, single-cell transcriptomics of neural stem cells derived from autism patients in vitro reveals recurrent changes in the expression of TFs that orchestrate brain patterning and neural stem cell lineage commitment.
This work opens up new possibilities for investigating disorders in the human brain in the early stages of development.
