Elacridar: Identification of the molecular target relevant to its anti-prion effects and its application to other protein misfolding neurodegenerative diseases

Prion diseases, while exceptionally rare, have provided a road map to link many protein misfolding neurodegenerative diseases in profound mechanistic ways including the prion-like spread of pathological protein aggregates from cell-to-cell and the neurotoxicity induced by soluble oligomers of these assemblies. Prion diseases also affect other animals, including model organisms (and immortalized cell lines), making them the only neurodegenerative disease that can be directly studied in laboratory experiments. This unprecedented scenario has allowed for the testing and characterization of small molecule therapeutics under real life conditions. We have recently discovered a novel anti-prion compound, elacridar, and preliminary data suggests that it exerts its effects through activating the lysosome, the organelle responsible for the degradation of unwanted proteins. Because of the central role of lysosomes to protein degradation, we extended these studies to determine that elacridar is also efficacious against misfolded α-synuclein and tau, proteins associated with more common neurodegenerative diseases. In this application, we propose experiments designed to define the mechanism of action whereby elacridar exerts its anti-prion effects through identification of the intracellular site(s) where it accumulates, the accompanying proteomic changes induced by this accumulation, and the identification of the molecular target responsible for these effects. We also propose to further explore the effects of elacridar against pathologically misfolded forms of α-synuclein and tau using assays to monitor their cell-to-cell spread, degradation, and neurotoxicity. We anticipate that the knowledge gained by these investigations will provide novel therapeutic targets for the treatment of neurodegenerative diseases.