Analysis of gene expression in neural cells subject to chronic proteasome inhibition

A number of studies have suggested that proteasome inhibition plays a causal role in the neuropathological processes observed in aging, Alzheimer's disease (AD), and Parkinson's disease (PD). Although the effects of acute and toxic proteasome inhibition on neural viability are well documented, at present little is known about the effects of chronic low-level proteasome inhibition on neural homeostasis. In order to address this issue we have established clonal lines of neural SH-SY5Y cells, which were generated after continual exposure to low concentrations of a pharmacological proteasome inhibitor. We have recently utilized these clonal cell lines to demonstrate that chronic low-level proteasome inhibition induces neural alterations that are highly relevant to aging, AD, and PD. The focus of this study was to elucidate the alterations in gene expression that occurred in our clonal cell lines after chronic low-level proteasome inhibition. Taken together, data presented in this report indicate that, although chronic low-level proteasome inhibition alters the expression of a limited number of genes (less than 0.8%), it is observed to significantly alter the expression of genes within specific categories that are highly relevant to aging, AD, and PD. Perhaps just as importantly, our analysis revealed that the vast majority of genes altered by chronic low-level proteasome inhibition have not been significantly characterized, suggesting that proteasome inhibition may mediate effects on neural homeostasis through as yet unidentified cellular processes.