Identification of regulatory proteins in conformational disorders

BIONDI, RICARDO M.; LEROUX, ALEJANDRO E.

Ciudad autonoma de Buenos aires

Simposio; Frontiers in Bioscience 3; 2018

Conformational disorders (CDs) are a group ofpathologies that share aggregation of specific proteins as a common feature andinclude the prion disease, Alzheimer?s disease, diverse tauopathies, and Parkinson?sdisease. There is no successful disease-modifying treatment yet available forany of the CDs, possibly because we lack detailed molecular understanding ofthe mechanisms that cause them. The seeding hypothesis is considered to be thegeneral mechanism explaining the aggregation of specific proteins in CDs.Nevertheless, even after 20 years of being accepted, aggregation by seedingremains vastly inefficient in cell-free assays. We postulate that there shouldbe additional common cellular mechanisms responsible for the aggregation ofspecific proteins. Defects in chaperone-assisted autophagy have been proposedto lead to protein aggregation. However, such mechanisms cannot explain theexistence of ?strains? of proteins that aggregate. Over the last 20 years, wefocused on the mechanism of regulation of protein kinases. The mechanisms usedby phosphoinositide-dependent protein kinase 1 (PDK1) in signaling requiresthat PDK1 senses the conformation of its substrates. Based on our work withPDK1, we elaborated a novel hypothesis that can explain how proteins aggregatein CDs and the existence of ?strains?. In preliminary work, we developed anovel cellular assay and confirmed our model: blocking the conformationalsensor pocket on PDK1 can trigger the aggregation of PKCzeta, establishing anew paradigm. The main goal of the project is to identify specificconformational sensors that are responsible for the cellular aggregation ofTau, a-synuclein, and p62/SQSTM1, all proteins that aggregate in CDs. Weenvisage that the identification of the conformational sensors and the actualmechanisms involved in protein aggregation will enable development ofinnovative drugs that target the original cause of major global diseases thathave high unmet medical need.