https://medicalxpress.com/news/2024-05-key-insights-potential-treatment-mental.amp
These investigations, conducted with colleagues from other major research centers, involve the largest single-cell analysis to date of the brains of people with schizophrenia, and a first-of-its-kind population-scale map of the regulatory components of the brain that provides critical insights into the pathogenesis of mental health disorders.
“We desperately need new directions for developing treatments for individuals with schizophrenia and other serious mental health illnesses,” says Panos Roussos, MD, Ph.D., senior author of both studies; Professor of Psychiatry, and Genetics and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai; and Director of the Center for Disease Neurogenomics.
“We now have the technology and methodology to do a deeper dive than ever before into the biology of neuropsychiatric diseases, and believe that through our latest research we have significantly advanced the field.”
Using a high-resolution dataset of 468,000 single-cell transcriptomes from 140 individuals, researchers looked for cell type-specific schizophrenia-dysregulated genes, pathways, and regulators. The result was a more comprehensive and highly detailed understanding of the molecular alterations associated with schizophrenia—in effect, a reframing of schizophrenia transcriptional pathology.
“While we observed gene change expression within all detected cell types, the majority occurred in neuronal populations and, specifically, more than three-quarters in excitatory neurons, which constitute the bulk of the brain’s neurons,” says Dr. Roussos, who led the analysis with John Fullard, Ph.D., Assistant Professor of Psychiatry, and Genetics and Genomic Sciences, at Icahn Mount Sinai.
The collaboration included partners from the Eli and Edythe L. Broad Institute of the Massachusetts Institute of Technology and Harvard, which allowed the team to compare independent findings from different patient cohorts to verify their consistency from one dataset to another.
“After pinpointing the molecular changes, we were able to look one level up to identify the transcription factorsthat drive many of those alterations,” explains Dr. Fullard. “That allowed us to identify important upstream regulators that could serve as targets for drug development.”
“As the field of gene therapy continues to progress, the linkage of risk loci for a wide range of psychiatric and neurological disorders with human brain regulatory regions holds great promise for therapeutic applications.”
Notably, Dr. Zeng adds, genome editing technologies such as CRISPR can potentially target regulatory elements and modify their activity, potentially restoring regulatory mechanisms to a pre-disease state. “The combination of population-scale regulome studies and advances in gene regulation,” he notes, “will undoubtedly provide important new avenues for treating brain disorders in the future.”