Suppression of FUS aggregation by proteasome inhibitors

Abstract

ALS (Amyotrophic Lateral Sclerosis) is characterized by aggregation of RNA-binding proteins, including FUS. The proteasome generally targets misfolded proteins for degradation, thereby limiting protein aggregation. Strikingly, we discovered that proteasome inhibitor treatment led to a significant suppression of ALS-associated mutant FUS aggregation in cells and primary neurons, in sharp contrast to its aggregation-promoting effects on other neurodegeneration-associated proteins. Our data revealed that proteasome inhibitors stimulated a unique transcriptional program, that selectively suppressed FUS aggregation. A key mediator of this program was the HSP70 co-chaperone BAG3, which markedly reduced FUS aggregation through selective autophagy. In parallel, the polyamine N1-acetyltransferase SAT1 was massively induced as part of this program, accompanied by remodeling of polyamine metabolism, and its metabolic activity was required for FUS aggregation suppression. Together, these findings reveal an unexpected protective response to proteasome inhibition that selectively suppresses FUS aggregation, which could be harnessed for future therapeutic intervention in FUS-ALS.

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