P3‐435: Modulation of the endosome‐to‐lysosome sorting pathway exerts neuroprotectivity in cellular and animal models of Parkinson's and Alzheimer's disease

Neuronal degeneration in Parkinson's and Alzheimer's disease entails an elusive cascade of events involving noxious aggregation of the amyloidogenic proteins α-synuclein and β-amyloid/TAU respectively. Therefore, inhibiting protein aggregation-associated cytotoxicity represents an effective strategy for decelerating or even halting disease progression. reMYND has used phenotypic screening approaches using yeast-based models of amyloidogenesis aimed for compounds that inhibit α-synuclein or TAU-associated cytotoxicity. Primary hits identified were subsequently validated and chemically optimized using neuronal models of noxious α-synuclein and TAU aggregation. Resulting lead compounds were used in proof-of-concept studies in animal models of Parkinson's and Alzheimer's disease. Currently, two chemical scaffolds - ReS9-S and ReS19-T - have been identified showing potent cytoprotective properties in a human neuronal cell model for PD and AD, respectively. Robust neuroprotective activity of lead compounds representing both compound families was demonstrated in mouse models of AD and PD. Biochemical analysis on brain extracts revealed that compounds from both the PD and AD programs reduced specifically membrane-associated alpha-synuclein and TAU, repectively. This activity may be therapeutically very relevant since protein-aggregation is not only facilitated by membrane structures but also disturbs its integrity and so setting-off a cascade of events (such as Golgi fragmentation as is observed in neurons early in disease) leading to neuronal degeneration. Mode-of-action studies in yeast and neuronal cell models were performed to reveal the pathway and to identify their corresponding molecular binding partners (targets) whose modulation by the compounds is responsible for the neuroprotective activity. Chemo-genetic and synthetic toxicity screening revealed that both molecules intervene in the endosome-to-lysosome sorting pathway by increasing vesicular-driven transport to lysosomes. The data suggests that ReS9-S and ReS19-T selectively and specifically facilitate lysosome-dependent clearance of pathological species of alpha-synuclein and TAU.