Small molecule induced proteolytic destruction of intrinsically disordered proteins

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The significance: There are still no effective treatments for neurodegenerative diseases, including Parkinson's and Alzheimer's disease and Alzheimer's related dementias. The problem: The pathogenesis of these disorders are driven in large part by the toxic signaling of amassed intrinsically disordered proteins (IDPs), such as α-synuclein or (phosphorylated)-tau, which have a high tendency to oligomerize and aggregate upon accumulation. During healthy homeostasis, IDPs are rapidly degraded by the 20S proteasome and thus are short-lived and in near undetectable abundance. As we age, proteasome activity is reduced and IDPs accumulate, leading to toxic signaling and aggregation, which are the hallmarks of many neurodegenerative diseases. These unfolded IDPs lack defined binding pockets, which made them evade traditional drug discovery design efforts and are therefore often deemed “undruggable”. Of all human organs and tissues, the brain expresses one of the highest levels of IDPs, and amassed levels of these highly disordered IDPs have been directly linked to neurodegenerative disorders. No effective treatments to prevent, stop or reverse these disorders are currently available. The solution: Enhancing 20S proteasome activity should restore healthy protein homeostasis and prevent the accumulation of disordered proteins. Our approach: Instead of inhibiting IDPs with a drug, we will induce their proteolytic destruction. Our hypothesis is that we can limit the toxic accumulation of IDPs by enhancing/restoring 20S proteasomal degradation using small molecules. This approach is different from all previous attempts to target IDP-instigated diseases. Our new data indicates that 20S proteasome enhancements exhibits selectivity towards the toxic, highly disordered oligomerization/aggregation-prone IDPs over other proteins that merely containing disordered regions. Moreover, our preliminary data shows that the treatments do not induce cytotoxicity in cells treated at high dose or following chronic exposure to the enhancers. 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.