mTOR inhibitor-independent Autophagy Activator Ameliorates Tauopathy and Prionopathy Neurodegeneration Phenotypes
Author:
Yoon LeonardORCID, Botham Rachel C., Verhelle Adriaan, Sanz-Martinez Pablo, Xu Jin, Cole Christian M., Tan Ee Phie, Chou Ching Chieh, Cuoco Caroline A., Massey Lynée A., Labra Sergio, Elia Lisa P., Ta Amina, Ardejani Maziar S., Lee Kyunga, Kline Gabriel M., Xiao Qiang, Cano-Franco Sara, Lyang Nora J., Hou William C., Yu Anan, Fox Susan, Ko Yeonjin, Wulkop-Gil Cristian, Ibrahim Lara H., Jiang Starr, Meneses Alina, Nelson Luke T., Peng Hongfan, Lipton Stuart A., Bollong Michael J., Hansen Malene, Morimoto Richard I., Petrassi H. Michael, Wiseman R. Luke, Powers Evan T., Finkbeiner Steven, Garza Danny, Finley Daniel, Prado Miguel A., Dikic Ivan, Frydman Judith, Johnson Kristen A., Silva M. Catarina, Haggarty Stephen J., Stolz Alexandra, Encalada Sandra E.ORCID, Kelly Jeffery W.ORCID
Abstract
SummaryAutophagy activation has the potential to ameliorate neurodegenerative disease phenotypes, including protein aggregation, lipid level perturbations and axonal trafficking defects. We performed a high content imaging-based screen assessing 940,000 small molecules to identify those that accelerate lipid droplet clearance. Hits were validated in diverse cell lines and by counter-screening. Of the 77 validated structurally diverse hits, 24 increase autophagy flux. Herein, we highlight CCT020312 as a mammalian target of rapamycin (mTOR) inhibitor-independent autophagy activator, which should function without suppressing the immune response. CCT020312 dose-dependently reduces cytotoxic axonal mutant prion protein aggregate levels within endosomes of primary murine hippocampal neurons and normalizes axonal trafficking deficiencies. Moreover, CCT020312 robustly clears phosphorylated insoluble tau, while reducing tau-mediated neuronal stress vulnerability in patient-derived neuronal models. CCT020312 also restores lysosomal function in neurons differentiated from sporadic Alzheimer’s patients fibroblasts bearing epigenetic marks of aging. Taken together, we describe a promising strategy to uncover novel pharmacological agents that normalize cellular neurodegenerative disease pathology.
Publisher
Cold Spring Harbor Laboratory
Cited by
4 articles.
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