Epilepsy is a common neurological disease worldwide, and one of its causes is genetic abnormalities. Here, we identified a point mutation in KIF4A, a member of kinesin superfamily molecular motors, in patients with neurological disorders such as epilepsy, developmental delay, and intellectual disability. KIF4 is involved in the poly (ADP-ribose) polymerase (PARP) signaling pathway, and the mutation (R728Q) strengthened its affinity with PARP1 through elongation of the KIF4 coiled–coil domain. Behavioral tests showed that KIF4-mutant mice exhibited mild developmental delay with lower seizure threshold. Further experiments revealed that the KIF4 mutation caused aberrant morphology in dendrites and spines of hippocampal pyramidal neurons through PARP1-TrkB-KCC2 pathway. Furthermore, supplementing NAD, which activates PARP1, could modulate the TrkB-KCC2 pathway and rescue the seizure susceptibility phenotype of the mutant mice. Therefore, these findings indicate that KIF4 is engaged in a fundamental mechanism regulating seizure susceptibility and could be a potential target for epilepsy treatment.
KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway
- Award Id(s): JP23000013,JP16H06372
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Yuansong Wan, Momo Morikawa, Manatsu Morikawa, Suguru Iwata, Muhammad Imran Naseer, Adeel Gulzar Ahmed Chaudhary, Yosuke Tanaka, Nobutaka Hirokawa; KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway. J Cell Biol 6 February 2023; 222 (2): e202208108. doi: https://doi.org/10.1083/jcb.202208108
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