Landscape of intrinsically disordered proteins in mental disorder diseases

Disrupted genes linked to mental disorders sometimes exhibit characteristics of Intrinsically Disordered Proteins (IDPs). However, few studies have comprehensively explored the functional associations between protein disorder properties and different psychiatric disorders. In this study, we collected disrupted proteins for seven mental diseases (MDD, SCZ, BP, ID, AD, ADHD, ASD) and a control dataset from normal brains. After calculating the disorder scores for each protein, we thoroughly compared the proportions and functions of IDPs between differentially expressed proteins in each disease and healthy controls. Our findings revealed that disrupted proteins, particularly in ASD and ADHD, contain more IDPs than controls from normal brains. Distinct patterns in disorder properties were observed among different mental disorders. Functional enrichment analysis indicated that IDPs in mental disorders were associated with neurodevelopment, synaptic signaling, and gene expression regulatory pathways. In addition, we analyzed the proportion and function of liquid-phase-separated proteins (LLPS) in psychiatric disorders, finding that LLPS proteins are mainly enriched in pathways related to neurodevelopment and inter-synaptic signaling. Furthermore, to validate our findings, we conducted an analysis of differentially expressed genes in an ASD cohort, revealing that the encoded proteins also exhibit a higher proportion of IDPs. Notably, these IDPs were particularly enriched in pathways related to neurodevelopment, including head development, a process known to be disrupted in ASD. Our study sheds light on the crucial role of IDPs in psychiatric disorders, enhancing our understanding of their molecular mechanisms.