In the present study, we demonstrate that raising cGMP and activating the cGMP-dependent kinase (PKG) can also stimulate 26S proteasomes and protein degradation, but in a manner distinct from PKA, and that these treatments also have beneficial effects in models of neurodegenerative diseases caused by an accumulation of mutant, misfolded proteins. Here, PRKG1 is linked to neurodegenerative disease.