Proteasome inhibition induces reversible impairments in protein synthesis

Abstract

Proteasome inhibition occurs during normal aging and in a variety of age-related diseases, with inhibition of proteasome function sufficient to induce physiological and pathological alterations observed in each of these conditions. It is presumed that proteasome inhibition induces cellular alterations by promoting rapid protein accumulation, as the direct result of impairments in protein removal, which assumes protein synthesis remains relatively unchanged during proteasome inhibition. We conducted experimentation using established proteasome inhibitors and primary rat neuron cultures in order to elucidate whether proteasome inhibition had any effect on neuronal protein synthesis. Proteasome inhibition impaired neuronal protein synthesis, with concentrations of inhibitor necessary to significantly inhibit protein synthesis similar to the concentrations necessary to induce subsequent neuron death. The inhibition of protein synthesis was reversible during the first 6 h of treatment, with the neurotoxicity of proteasome inhibition reversible during the first 12 h of treatment. These studies are the first to demonstrate a potentially important interplay between the proteasome and protein synthesis in neurons, and the first to identify that some effects of proteasome inhibition are reversible in neurons. Together these findings have important implications for understanding proteasome inhibition as a potential contributor to aging and age-related disease.