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

Abstract

The cellular response to brain injury mediates the fate of the neuron. Previous studies to identify neuronal responses that could be protective indicated intracellular transport as a potential target, but the underlying mechanisms are still unknown. Here, we showed that a decreased level of kinesin-1, a microtubule-dependent molecular motor, confers neuroprotection by reducing extrasynaptic N-methyl-D-aspartate receptor (NMDAR) targeting and functioning. We found that kif5b, the heavy chain of kinesin-1, was down-regulated by ischemic preconditioning. A loss of 50% of Kif5b protected the neurons against excitotoxic insult and ischemia provoked neurodegeneration through the hypofunction of NMDARs. Kinesin-1 forms complex with NMDAR in vivo and the tail of Kif5b directly binds with the NR2B cytoplasmic tails. Decreased kinesin-1 reduces the formation of this complex in vivo, prevents NMDAR concentrating at extrasynaptic sites and inhibits calcium influx mediated by extrasynaptic NMDAR activation to confer neuroprotection. De novo upregulation of the reduced Kif5b level abolished such protection effects. Our findings reveal 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.