2016 to 2019
Alzheimer’s disease and several other neurodegenerative diseases are associated with the accumulation in neurons of misfolded aggregation-prone proteins (e.g., tau and amyloid beta). Presently, no treatment is available to slow the steady accumulation of such toxic proteins. Such misfolded proteins in cells typically are selectively destroyed by the proteasome (the primary site of protein breakdown in our cells). There is growing evidence that this enzymatic system becomes defective in these diseases, apparently because protein aggregates can disrupt proteasome functioning. This research seeks to identify novel pharmacological agents that activate the 26S proteasome and stimulate the degradation of such misfolded, toxic proteins.
Our lab has identified three cellular signaling systems that can be activated by drugs and that can stimulate the cell’s capacity to destroy misfolded proteins. We had found previously that agents that raise the level of the signaling molecule cyclic adenosine monophosphate (cAMP) cause a chemical modification of the proteasome that enhances its activity. Moreover, such agents could restore proteasome activity and stimulate the clearance of tau in brains of a mouse model of Alzheimer’s disease. We recently demonstrated that another important cellular signaling molecule, cyclic GMP, also can stimulate protein breakdown by modifying the proteasome in distinct ways from cAMP. We have focused on the promising effects of cGMP because drugs that raise cGMP are widely used in medicine. Furthermore, in zebrafish models of Alzheimer’s and Huntington’s diseases and in a mouse model of a human peripheral neuropathy (Charcot-Marie-Tooth Disease 1b), drugs that raise cGMP stimulated proteasome activity, decreased the levels of the disease-causing mutant proteins, and reduced neuronal death and the associated pathology. We now hope to further clarify the mechanisms for these promising drug actions and to test whether other agents that raise cGMP or activate protein kinase C also enhance the clearance of pathogenic proteins and therefore may be useful therapies for these diseases.
Alzheimer’s disease (AD) and several other neurodegenerative diseases often are caused by the accumulation in neurons of misfolded aggregation-prone proteins, including tau and amyloid beta. Presently, no treatment is available to slow the steady accumulation of such toxic proteins. Normally, misfolded proteins in cells are selectively destroyed by the proteasome—the primary site of protein breakdown in our cells. There is growing evidence that proteasome function becomes defective during neurodegeneration in large part due to protein aggregates that disrupt function. This research seeks to understand the biochemical adaptations by which neurons can compensate for impairments in proteasome function and slow disease progression. The primary goal will be to identify novel pharmacological agents that activate the 26S proteasome and stimulate the degradations of such misfolded, potentially toxic proteins. In research from our lab, we demonstrate that drugs that stimulate proteasome activity, decreased the levels of the disease-causing mutant proteins, reduced neuronal death, and the associated pathology. This evidence indicates that proteasome activation is a potential approach for the treatment of Alzheimer’s disease. In future research, we hope to clarify the mechanisms of actions for these drugs and test whether other agents can clear the pathogenic protein.
2016 – 2017
It has been widely assumed that rates of degradation of proteins by the ubiquitin-proteasome system (UPS) are regulated solely at the ubiquitination step. We recently discovered a novel biochemical mechanism, proteasome phosphorylation, that cells utilize to enhance their capacity to degrade misfolded proteins, such as mutant tau and phospho-tau (p-tau). We have shown that the 26S proteasome’s capacity to degrade ubiquitinated proteins is enhanced in cells and mouse brains by agents (e.g. inhibitors of phosphodiesterase 4) that raise cAMP and activate PKA-dependent phosphorylation of a subunit of the proteasome’s 19S regulatory complex, Rpn6/PSMD11. These new insights into the mechanisms regulating proteasome function and the degradation of misfolded proteins indicate a very promising approach for development of novel drugs to inhibit the progression of Alzheimer’s Disease (AD) and other tauopathies. Moreover, such treatments are potentially applicable to other neurodegenerative diseases caused by the accumulation of aggregation-prone proteins. Also these approaches build on the well-characterized cAMP-PKA signaling pathway, and a variety of phosphodiesterase 4 (PDE4) inhibitors have been developed that raise cAMP levels in cells. Because our recent studies also indicate that proteasome function in several disease models is somehow inhibited by the accumulation of aggregated proteins, it seems likely that impaired proteostasis contributes to disease pathogenesis. Consequently, pharmacological activation of proteasomes should directly counter this important disease mechanism and merits further in-depth study. Although PDE4 inhibitors appear to be a very promising means to promote clearance of mutant tau and to enhance memory, such agents can have undesirable side effects. One immediate goal of these studies is to compare the efficacy of different PDE4 inhibitors in activating brain proteasomes. We also shall test if other cyclic nucleotides and other cellular kinases have a similar capacity to activate 26S proteasomes and promote the clearance of mutated proteins. Additional studies will attempt to clarify how protein aggregates can impair proteasome function and how neurons may compensate for the impaired proteostasis.