The Anti-Neuron-Specific Enolase Antibody Induced Neuronal Cell Death in a Novel Fashion

Suppression of ubiquitin proteasome pathway (UPP) and stimulation of caspase-3 are involved in neurodegeneration. Can UPP activators and caspase-3 inhibitors ameliorate neurodegeneration? Here, we found a novel neuronal cell death accompanied with UPP activation and caspase-3 inhibition. Recently, plasmalemmal neuron-specific enolase (NSE) has been identified as one of membrane targets of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). 15d-PGJ2 induces neuronal apoptosis via activating caspase-3 and inactivating UPP, whereas the anti-NSE antibody inactivated caspase-3, activated UPP, and caused neuronal cell death. The anti-NSE antibody activated caspase-1 (pyroptosis marker), but not condense chromatin (apoptosis marker). The anti-NSE antibody declined intracellular level of ATP, which is not altered in pyroptosis. The intracellular level of calcium is elevated in necrosis and pyroptosis, but its chelator did not ameliorate the neurotoxicity of anti-NSE. Thiol antioxidants such as N-acetyl cysteine and glutathione reduced the neurotoxicity of 15d-PGJ2 but enhanced that of the anti-NSE antibody. The anti-NSE antibody incorporated propidium iodide into neurons through the disrupted plasma membrane, which are not observed in ferroptosis and autophagic cell death. Thus, the anti-NSE antibody induced neuronal cell death in a novel fashion distinguished from necrosis, necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagic cell death.