PRPF40B regulates NTRK2 pre-mRNA splicing to control its dominant-negative receptor, preventing BDNF signaling inhibition in neurons

BDNF signaling through its receptor TRKB plays a critical role in brain development, neuroplasticity, and maintaining homeostasis. The TRKB gene, NTRK2, encodes both the full-length receptor (TRKB-FL) and a truncated isoform (TRKB-T1) generated by alternative splicing, which acts as a dominant-negative mutant, inhibiting TRKB-FL signaling. Dysregulation of BDNF-TRKB signaling, including TRKB-T1 upregulation, has been observed in neurodegenerative diseases, psychiatric disorders, and cognitive impairments. Here, we show that PRPF40B, a splicing factor associated with neuronal dysfunctions, regulates the TRKB-FL/TRKB-T1 balance during neuronal differentiation by modulating splicing. Silencing PRPF40B increases the TRKB-T1 expression, impairing neuronal differentiation and synaptic plasticity. Our data identify PRPF40B as a key regulator of the TRKB receptor balance, crucial for fine-tuning neuronal responses and preventing neuroplasticity or survival impairments. Overall design: RNA-seq profiling of SH-SY5Y neuroblastoma wild-type (WT) and their knockdown derivatives (Scramble and G2).