Discovery of Proteins and Metabolites Implicated in Mental Illness and Neurodevelopmental Disorders
Presenter
Laurie Nadler, Ph.D.
Division of Neuroscience and Basic Behavioral Science
Goal
The goal of this concept is to determine changes in protein expression, post-translational modifications, protein-protein interactions, and/or metabolite abundance in human postmortem brain and human-derived cells across development and as a function of mental illness and/or neurodevelopmental disorders.
Rationale
From 2014-2024, the NIMH PsychENCODE Consortium (PEC) generated a comprehensive resource of gene expression (transcriptomics) and gene regulation (chromatin activity) in the human brain across disease states, brain regions, cell types, and developmental epochs. While the PEC had a major impact on the field of psychiatric genetics, leading to two sets of landmark papers in 2018 and 2024, our understanding of the signaling pathways underlying mental illness and neurodevelopmental disorders remains limited as such pathways must be inferred from genomic and transcriptomic data. Due to regulation at the levels of mRNA degradation and protein synthesis, mRNA expression does not correlate strongly with protein expression, nor does it reliably predict dynamic signaling pathways involved in biological function or disease.
Proteins, encoded by genes, as well as small molecule metabolites, carry out crucial cellular functions. Full understanding of the biological pathways altered by psychopathology will require investigation of protein expression, post-translational modifications (e.g., phosphorylation, glycosylation, ubiquitination), protein-protein interactions, and metabolite abundance. To date, few proteomic studies of mental illness and neurodevelopmental disorders in human postmortem brain or human-derived cells have been conducted, highlighting the gap in our understanding of how genetic variation leads to altered molecular cascades underlying psychopathology.
The proposed concept would target the gap in our understanding of biological pathways altered in mental illness and neurodevelopmental disorders by determining changes in protein expression, post-translational modifications, protein-protein interactions, and/or metabolite abundance in human postmortem brain and human-derived cells across development and as a function of disease. Research related to this concept may include, but is not limited to, mass spectrometry-based analyses of well-characterized human postmortem brain tissue or human-derived cells from individuals with mental illness and/or neurodevelopmental disorders versus healthy controls. Bioinformatic approaches would integrate the proteomic and metabolomic data with existing functional genomic data to generate a foundational public resource of multi-omic knowledge about networks and pathways in specific regions and cell types of the human brain that correlate with development, mental illness, and neurodevelopmental disorders. Data would also be harmonized within and across projects. This comprehensive dataset would lead to the generation of well-informed, testable hypotheses about dynamic cellular and molecular mechanisms of mental illness and neurodevelopmental disorders, and may lead to the identification of new therapeutic targets. The proposed concept complements efforts supported by the BRAIN Initiative Cell Atlas Network (BICAN ) and the Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene ) Consortium, in which few proteomic projects and no metabolomic projects currently exist.