TARGETING CHAPERONES TO TREAT FTLD

Abstract

The microtubule-associated protein tau becomes neurotoxic in Alzheimer's disease and frontotemporal dementia. Finding therapeutics to remove this abnormal tau is needed. Small molecule-based drug discovery targeting tau is in its early stages, but major efforts are underway to accelerate this. Currently only one small molecule, a phenothiazine derivative, is in phase III clinical trials. The putative mechanism for this compound is direct inhibition of tau aggregation, but we found that this class of small molecules also blocks chaperones from preserving tau, leading to its clearance. This suggested that common structural properties govern tau aggregation and chaperone binding. We have used several techniques to evaluate the effects of chaperone inhibitors and their potential synergy with aggregation inhibitors. We have employed cell culture, biochemical, biophysical and ex vivo slice culture strategies to survey the efficacy of approaches that target chaperones alone or in combination with aggregation inhibitors. We have also employed electrophysiology to further explore the effect of this approach on restoring tau-mediated synaptic deficits. We recently discovered the molecular basis for tau interacting with Hsp90, providing the first demonstration of how a client interacts with this important chaperone. Through this and other work, we have determined that the same amino acid sequences in tau are required for both its aggregation and its binding to chaperones. Indeed compounds that inhibit tau aggregation and chaperone function are the most potent for reducing tau and rescuing synaptic deficits caused by tau accumulation. The basis for this mechanism of action is that chaperones have greater access to tau when it is unable to aggregate, creating more chaperone/tau complexes that can be targeted for degradation with inhibitors. We observed this same principle of competition for tau binding when we found that microtubule destabilization also enhanced tau binding to chaperones. While a chaperone/tau interface is potentially “druggable”, one of the biggest concerns with chaperone-based therapies is both the on- and off-target toxic liabilities. Perhaps by exploiting our understanding of tau aggregation and tau's interaction with chaperones, we can lower the doses required for efficacy of either drug, reducing the chances for detrimental side-effects.