The significance: There are still no effective treatments for Alzheimer?s disease and Alzheimer?s disease related dementias. The problem: The pathogenesis of Alzheimer?s disease is driven in large part by the toxic signaling of amassed intrinsically disordered proteins (IDPs), such tau, which has a high tendency to aggregate upon accumulation. In addition to its tendency to aggregate upon accumulation, these unfolded IDPs lack defined binding pockets, thus they have largely evaded traditional drug discovery design efforts and are often deemed ?undruggable?. During healthy homeostasis, IDPs are short-lived and in low-to-undetectable quantity, because IDPs are unremittingly proteolytically degraded by the 20S proteasome. However, when IDP production outpaces its degradation (due to gene amplification, mutation or other cellular dysfunctions including a decrease in proteasome function), their subsequent accumulation can lead to harmful signaling. Of all human organs and tissues, the brain expresses one of the highest levels of IDPs, and over-expression of certain IDPs have been directly linked to these neurodegenerative disorders. The solution: Recent ground breaking studies found that enhancing proteasome activity can prevent toxic accumulation of IDPs, reduce brain damage and prevent dementia. Our approach: Our hypothesis is that we can reduce toxic levels of over-expressed IDPs by enhancing/restoring 20S proteasomal degradation using small molecules. Instead of inhibiting IDPs with a drug, we will induce their proteolytic destruction by developing small molecules that enhance 20S proteasome activity. This approach is different from all previous attempts to target IDP-instigated diseases. Consistent with the low-to-undetectable levels of IDPs during healthy homeostasis, we found that enhancing 20S proteasome-mediated proteolysis has a minimal effect on normal cellular functions. This is an unexplored field in science and human health and we will be one of the first to determine the possibilities and limitations of this new approach in this work.
The goal of this work is to evaluate the use of small molecules to enhance the catalytic degradation of a specific class of ?undruggable? proteins, referred to as intrinsically disordered proteins. When over-expressed, these disordered proteins are directly implicated in many human diseases, including neurodegenerative diseases such as Parkinson's and Alzheimer's disease and Alzheimer's related disorders. This work will critically evaluate this new approach in terms of its potential, as well as its limitations, as a completely new therapeutic strategy to treat these incurable diseases.