The ubiquitin proteasome system (UPS) degrades the majority of proteins in mammalian cells and one of its primary functions is to selectively eliminate misfolded, potentially toxic proteins. In the UPS, protein substrates are modified by the attachment of chains of ubiquitin molecules, which target the protein for rapid degradation by the 26S proteasome. It is generally assumed that ubiquitination determines the rate of protein degradation by the UPS, but recent studies have shown that the activity of 26S proteasomes is tightly regulated and can determine rates of protein degradation in cells. Our lab and collaborators recently found that agents that raise cAMP cause the Protein Kinase A-mediated phosphorylation of the 26S subunit Rpn6 and the enhancement of multiple proteasome activities. This modification increases the capacity in cells and mouse brains to degrade misfolded, aggregation-prone proteins (e.g. mutant Tau and SOD1) that cause neurodegenerative diseases. Thus, pharmacological enhancement of proteasome function is an exciting new approach to combat various aging-associated diseases. I recently found that treatments that raise cGMP and activate Protein Kinase G also stimulate proteasome activity and protein degradation in cells. This cGMP-mediated stimulation was not due to Rpn6 phosphorylation, and therefore occurs by a different mechanism than raising cAMP. I am proposing an in-depth investigation to determine 1.) how raising cGMP stimulates proteasome function, 2.) the effect of raising cGMP on the degradation of different types of cell proteins and 3.) whether FDA-approved pharmacological agents that increase cGMP levels (e.g. PDE5 inhibitors) enhance the clearance of mutant proteins that cause Alzheimer?s Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Parkinson?s Disease. These studies should clarify the mechanisms and importance of this new mode of regulating protein degradation and its therapeutic potential.
Our lab and collaborators demonstrated that pharmacological agents that raise cAMP stimulate proteasome activity through Protein Kinase A-mediated phosphorylation of proteasome subunit Rpn6. My unpublished findings show that cGMP and Protein Kinase G, through a mechanism independent of Rpn6 phosphorylation, can also stimulate 26S proteasome activity and intracellular protein degradation. My goal is to define the biochemical mechanisms by which proteasomes are activated by cGMP and determine whether FDA-approved pharmacological agents that raise cGMP have the therapeutic potential to stimulate the clearance of toxic proteins that accumulate in aging-related diseases, especially neurodegenerative diseases (e.g. Alzheimer?s, Frontotemporal Dementia, and other Tauopathies).
