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Activation of the 26S Proteasome for the Treatment of Alzheimer’s Disease

Funding year(s): 
2016 to 2017
Funding to date: 
$300,000

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.