Zinc neurotoxicity to hippocampal neurons in vitro induces ubiquitin conjugation that requires p38 activation.

There is increasing evidence showing that zinc plays a key role in inducing neuronal death during central nervous system injury. However, the underlying mechanisms are poorly understood. Here we assessed the effect of zinc on ubiquitin conjugation and subsequent neurodegeneration using cultured hippocampal cells. We report that cultured neurons are vulnerable to increased level of extracellular Zn²⁺. Zn²⁺-induced poly-ubiquitination in cultured neurons is in a concentration- and time-dependent manner. Furthermore our data demonstrated that Zn²⁺-induced ubiquitination requires p38 activation. These findings indicate that excessive zinc could impair the protein degradation pathway and may be a crucial factor mediating neuronal death following traumatic brain injury.