Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 294, Issue: 50, Page: 18952-18966
2019
- 88Citations
- 191Captures
- 2Mentions
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Metrics Details
- Citations88
- Citation Indexes86
- 86
- CrossRef44
- Patent Family Citations2
- Patent Families2
- Captures191
- Readers191
- 191
- Mentions2
- News Mentions2
- News2
Most Recent News
Image of the Day: Tau Aggregation
Endolysosome leakiness allows tau to build up in cells.
Article Description
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.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0021925820308127; http://dx.doi.org/10.1074/jbc.ra119.009432; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85076504495&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/31578281; https://linkinghub.elsevier.com/retrieve/pii/S0021925820308127; https://dx.doi.org/10.1074/jbc.ra119.009432
Elsevier BV
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