Regulation of NTRK2 alternative splicing by PRPF40B controls neural differentiation and synaptic plasticity

  • Cell Death Dis. 2025 Dec 8;17(1):73. doi: 10.1038/s41419-025-08301-9.
María Duarte-Ruiz  1 ,  Adela Moreno-Castillo  1 ,  Younes El Yousfi  2 ,  Cristina Moreno-Castro  3 ,  Noelia Martínez-Martínez  1  4 ,  Sandra Jiménez-Lozano  1 ,  Marion Kennel  1 ,  Candela Ruiz-Rodríguez  5 ,  Alonso Rodríguez-Caparrós  5 ,  Jennifer López-Ros  5 ,  Pierre de la Grange  6 ,  Cristina Hernández-Munain  5 ,  Carlos Suñé  7
Affiliations
  • 1. Department of Molecular Biology, Institute of Parasitology and Biomedicine "López Neyra" (IPBLN-CSIC), Granada, Spain.
  • 2. Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain.
  • 3. ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
  • 4. Department of Pharmacy and Pharmaceutical Technology, and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
  • 5. Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine "López Neyra" (IPBLN-CSIC), Granada, Spain.
  • 6. GenoSplice, Paris, France.
  • 7. Department of Molecular Biology, Institute of Parasitology and Biomedicine "López Neyra" (IPBLN-CSIC), Granada, Spain. [email protected].
PMID: 41360765 DOI: 10.1038/s41419-025-08301-9
Abstract

BDNF signaling through its receptor TrkB plays a critical role in brain development, neuroplasticity, and homeostasis. Alternative splicing of the TrkB gene, NTRK2, generates either the full-length receptor (TRKB-FL) or a truncated isoform (TRKB-T1) that inhibits BDNF signaling and has been implicated in neurodegenerative diseases, psychiatric disorders, and cognitive impairments. Here, we show that PRPF40B, a splicing factor associated with neuronal dysfunction, promotes the production of the TRKB-FL isoform during neuronal differentiation. Silencing PRPF40B increases TRKB-T1 expression and impairs the expression of genes important for neuronal differentiation and synaptic plasticity, both in vitro and in vivo, during early embryogenesis. Our data thus identify PRPF40B as a key regulator of the balance between TrkB receptor isoforms, crucial for fine-tuning neuronal responses and for preventing neuroplasticity or survival impairments, providing also a mechanism for the role of PRPF40B in the pathogenesis of various human neurodegenerative diseases and psychiatric disorders.