FRMD5 as a Molecular Hub Altering GR Functions in PTSD

Post-traumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder with limited intervention targets. FRMD5, a scaffold protein, serves as molecular hub involved in diverse biological processes. This study elucidates a tissue-specific mechanism via shorter isoform of FRMD5, characterized by condensate formation and special interactive features, on modulation of glucocorticoid receptor (GR) transcriptional functions. Using a comprehensive set of techniques, we observed a reduction in stress-induced behaviors, highlighting the crucial role of shorter isoform of FRMD5. Further investigations revealed that shorter isoform of FRMD5 forms condensates in nuclear and interacts with a set of proteins involved in GR protein complex and transcriptional cofactors. Besides, FRMD5 accelerates the nuclear translocation and modulates transcriptional functions of GR. Systemic administration of peptides that disrupt FRMD5 functions led to transcriptional functions changes of GR and decreased stress-induced behaviors in mice. Overall, this study uncovers an intrinsic mechanism modulating transcriptional functions of GR via specific FRMD5 isoform, identifying a potential intervention target for PTSD. Overall design: RNA-seq profiling of L929 cell lines with truncated FRMD5 (Isoform 2) after 4 hours DEX treated, and primary neurons of mice with interfering peptide after DEX treated.