Kinesin-1 regulates extrasynaptic NMDAR targeting and its reduction can confer neuroprotection

Abstract

The cellular response to brain injury influences the fate of the neuron. Previous studies to identify potential neuroprotective responses indicated intracellular transport as a potential target, but the underlying mechanisms are still unknown. In this study, it showed that a decreased level of kinesin-1, a microtubule-based molecular motor, confers neuroprotection by reducing extrasynaptic N-methyl-Daspartate receptor (NMDAR) targeting and functioning. The protein level of KIF5B, the heavy chain of kinesin-1, was found to be down-regulated by ischemic preconditioning. A decrease of 50% of KIF5B protected the neurons against glutamate insult and ischemia-provoked neurodegeneration through reducing the level of extrasynaptic NMDARs. Kinesin-1 forms complex with NMDAR in vivo and the tail of KIF5B directly binds with the cytoplasmic tails of the GluN1 and GluN2B subunits. Amino acids 907-915 was found to be the NMDAR-binding core in KIF5B, and the electrostatic force and the hydrophobic/hydrophilic state within this core may be essential for KIF5B to bind with NMDAR. Deletion of the binding domain within KIF5B abolished its interaction with NMDAR. Decreased kinesin-1 reduced the formation of this complex and prevented NMDAR concentrating at extrasynaptic sites to confer neuroprotection. De novo upregulation of the reduced KIF5B level abolished such protection effects while disrupting KIF5B’s interaction with NMDAR retained the protection effects. The findings revealed that kinesin-1 reduction benefits and protects the neurons against neurodegeneration by reducing the cellular response to NMDAR mediated excitotoxic insult, which is likely to be an intrinsic event in the early stage of neurodegeneration. This finding could lead to the development of therapeutic strategies that fine-tune the intracellular transport machinery to postpone or halt neurodegeneration.