cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases

Most studies of the regulation of proteolysis by the ubiquitin proteasome system have focused on the control of ubiquitination. However, it is now clear that the activity of the 26S proteasome and rates of protein degradation in cells are also tightly regulated through proteasome phosphorylation. Here we demonstrate that agents that raise cGMP and activate cGMP-dependent protein kinase (e.g., widely used phosphodiesterase 5 inhibitors) stimulate proteasome activities and intracellular proteolysis without affecting autophagy. Furthermore, we showed that raising cGMP reduced the levels of the disease-causing mutant tau in a zebrafish model by increasing its degradation, and also decreased the associated morphological abnormalities. Thus, activating the proteasome via cGMP is a promising strategy to prevent the progression of neurodegenerative diseases.