Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation.

1. J Biol Chem. 2019 Dec 13;294(50):18952-18966. doi: 10.1074/jbc.RA119.009432. Epub 2019 Oct 2. Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation. Chen JJ(1), Nathaniel DL(1), Raghavan P(2), Nelson M(1)(3), Tian R(1)(4), Tse E(1), Hong JY(1), See SK(1)(5), Mok SA(1), Hein MY(6), Southworth DR(1)(7), Grinberg LT(8), Gestwicki JE(1)(9), Leonetti MD(2), Kampmann M(10)(2)(7). Author information: (1)Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94158. (2)Chan Zuckerberg Biohub, San Francisco, California 94158. (3)Biomedical Sciences Graduate Program, University of California, San Francisco, California 94158. (4)Biophysics Graduate Program, University of California, San Francisco, California 94158. (5)Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, California 94158. (6)Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158. (7)Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158. (8)Department of Neurology, University of California, San Francisco, California 94158. (9)Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158. (10)Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94158 martin.kampmann@ucsf.edu. Intercellular propagation of protein aggregation is emerging as a key mechanism in the progression of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia (FTD). However, we lack a systematic understanding of the cellular pathways controlling prion-like propagation of aggregation. To uncover such pathways, here we performed CRISPR interference (CRISPRi) screens in a human cell-based model of propagation of tau aggregation monitored by FRET. Our screens uncovered that knockdown of several components of the endosomal sorting complexes required for transport (ESCRT) machinery, including charged multivesicular body protein 6 (CHMP6), or CHMP2A in combination with CHMP2B (whose gene is linked to familial FTD), promote propagation of tau aggregation. We found that knocking down the genes encoding these proteins also causes damage to endolysosomal membranes, consistent with a role for the ESCRT pathway in endolysosomal membrane repair. Leakiness of the endolysosomal compartment significantly enhanced prion-like propagation of tau aggregation, likely by making tau seeds more available to pools of cytoplasmic tau. Together, these findings suggest that endolysosomal escape is a critical step in tau propagation in neurodegenerative diseases. © 2019 Chen et al. DOI: 10.1074/jbc.RA119.009432 PMCID: PMC6916486 PMID: 31578281 [Indexed for MEDLINE] Conflict of interest statement: The authors declare that they have no conflicts of interest with the contents of this article