mTOR inhibitor-independent Autophagy Activator Ameliorates Cellular Tauopathy and Prionopathy Neurodegeneration Phenotypes

• Published in: bioRxiv
• Main Authors: Yoon, Leonard, Botham, Rachel C, Verhelle, Adriaan, Cole, Christian, Tan, Ee Phie, Wu, Yin, Sanz-Martinez, Pablo, Xu, Jin, Cuoco, Caroline A, Chou, Ching Chieh, Labra, Sergio, Elia, Lisa P, Massey, Lynee A, Lee, Kyunga, Xiao, Qiang, Kline, Gabriel M, Ta, Amina, Ardejani, Maziar S, Cano-Franco, Sara, Lyang, Nora J, Hou, William C, Yu, Anan, Fox, Susan, Ko, Yeonjin, Chen, Wenbo, Wulkop-Gil, Cristian, Ibrahim, Lara H, Starr, Jiang, Meneses, Alina, Nelson, Luke T, Peng, Hongfan, Lipton, Stuart A, Bollong, Michael J, Hansen, Malene, Morimoto, Richard I, Finley, Daniel, Petrassi, H Michael, R Luke Wiseman, Powers, Evan T, Finkbeiner, Steven, Garza, Dan, Prado, Miguel A, Dikic, Ivan, Frydman, Judith, Johnson, Kristen A, Silva, M Catarina, Haggarty, Stephen J, Stolz, Alexandra, Encalada, Sandra E, Kelly, Jeffery W
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 30.09.2022
• Subjects: Aging; Alzheimer's disease; Autophagy; Cell lines; Cytotoxicity; Endosomes; Epigenetics; Fibroblasts; Hippocampus; Immune clearance; Immune response; Neurodegeneration; Neurodegenerative diseases; Phenotypes; Prion protein; Protein interaction; Rapamycin; Tau protein; TOR protein
• DOI: 10.1101/2022.09.29.509997

Autophagy 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 structurally diverse validated hits, 24 increase autophagy flux. Herein, we highlight CCT020312 as a mammalian target of rapamycin (mTOR) inhibitor-independent autophagy activator, which should function without compromising human immune function. 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. Competing Interest Statement The authors have declared no competing interest.