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July 25th, 2025 - Press release

Linking alterations in precursor cells of brain formation with the origin of neuropsychiatric diseases

Researchers from the Hospital del Mar Research Institute and Yale University, in the United States, have demonstrated how the action of certain genes on precursor cells of brain formation can cause alterations linked to cortical malformations but also to the origin of neuropsychiatric diseases such as autism or bipolar disorder.

The study, published in Nature Communications, is the first of its kind. It has been able to simulate the function of a list of nearly 3,000 genes linked to these pathologies during human brain development.

The work opens a window to understand the origin of these diseases and to develop treatment opportunities through gene therapy.

The origin of some neuropsychiatric diseases, such as autism, bipolar disorder, or depression, and certain neurodegenerative diseases, Alzheimer's and Parkinson's, can be found in very early stages of brain formation in the fetus. That is, earlier than previously recognized, according to a study by the Hospital del Mar Research Institute and Yale University, published in Nature Communications.

Left to right, Xoel Mato-Blanco, Gabriel  Santpere

The work focused "on searching for the origin of mental illnesses in the earliest stages of fetal development, especially in the brain stem cells", explains Dr. Gabriel Santpere, Miguel Servet researcher and coordinator of the Neurogenomics Research Group at the Biomedical Informatics Research Program of the Hospital del Mar Research Institute, a joint group with Pompeu Fabra University. To do this, they used a list of nearly 3,000 genes linked to neuropsychiatric diseases, neurodegenerative pathologies, and cortical malformations, and simulated the effect of their alteration on the cells involved in brain development. The results indicate that many of these genes are already functional during the initial phases of fetal development in stem cells, the progenitors that build the brain, creating neurons and their supporting structures.

Achieving this was not easy. This moment of brain development is very difficult to study. For this reason, the researchers combined multiple data from human and mouse brains, as well as in vitro cellular models. As Dr. Nicola Micali, associate researcher at Dr. Pasko Rakic's lab at Yale University and co-leader of the research, points out, "scientists usually study the genes of mental illnesses in adults, but in this work we discovered that many of these genes already act during the early stages of fetal brain formation, and that their alterations can affect brain development and promote mental disorders later on".

During the study, specific regulatory networks for each cell type involved in brain development were simulated to see how the activation or deactivation of the analyzed genes linked to various brain diseases affected progenitor cells in their different stages. This allowed them to observe the importance of each gene in the emergence of alterations that cause various diseases. The list ranges from microcephaly and hydrocephaly to autism, depression, bipolar disorder, anorexia, or schizophrenia, and also includes Alzheimer's and Parkinson's.

In all these pathologies, genes involved in the earliest phases of brain development when neural stem cells are functional are found. "We cover a wide spectrum of diseases that the brain can have and look at how the genes involved in these conditions behave in neural stem cells", adds Xoel Mato-Blanco, researcher at the Hospital del Mar Research Institute. At the same time, he points out that the work "identifies temporal windows and cell types where the action of these genes is most relevant, indicating when and where you should target the function of these genes".

Having this information "is useful to understand the origin of diseases that affect the cerebral cortex, that is, how genetic alterations translate into these pathologies", says Dr. Santpere. Understanding these mechanisms and the role of each gene in each disease can help develop targeted therapies that act on them, opening opportunities for gene therapy and personalized treatments.

Reference article

Mato-Blanco, X., Kim, SK., Jourdon, A. et al. Early developmental origins of cortical disorders modeled in human neural stem cells. Nat Commun 16, 6347 (2025). https://doi.org/10.1038/s41467-025-61316-w