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

Duarte-Ruiz, M.; Moreno-Castillo, A.; El Yousfi, Y.; Moreno-Castro, C.; Martinez-Martinez, N.; Jimenez-Lozano, S.; Kennel, M.; Ruiz-Rodriguez, C.; Rodriguez-Caparros, A.; Lopez-Ros, J.; de la Grange, P.; Hernandez-Munain, C.; Sune, C.

doi:10.1101/2025.04.07.647526

bioRxiv · 10.1101/2025.04.07.647526

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

Duarte-Ruiz, M.·Moreno-Castillo, A.·El Yousfi, Y.·Moreno-Castro, C.·Martinez-Martinez, N.·Jimenez-Lozano, S.·Kennel, M.·Ruiz-Rodriguez, C.·Rodriguez-Caparros, A.·Lopez-Ros, J.·de la Grange, P.·Hernandez-Munain, C.·Sune, C.

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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 production of the TRKB-FL isoform during neuronal differentiation. Silencing PRPF40B increases TRKB-T1 expression, impairing expression of genes important for neuronal differentiation and synaptic plasticity. 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

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Duarte-Ruiz, M., Moreno-Castillo, A., El Yousfi, Y., Moreno-Castro, C., Martinez-Martinez, N., Jimenez-Lozano, S., Kennel, M., Ruiz-Rodriguez, C., Rodriguez-Caparros, A., Lopez-Ros, J., de la Grange, P., Hernandez-Munain, C., Sune, C.. 2025-04-07. Regulation of NTRK2 alternative splicing by PRPF40B controls neural differentiation and synaptic plasticity. https://doi.org/10.1101/2025.04.07.647526

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