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

John J Chen,Diane L Nathaniel,Preethi Raghavan,Maxine Nelson,Ruilin Tian,Eric Tse,Jason Y Hong,Stephanie K See,Sue-Ann Mok,Marco Y Hein,Daniel R Southworth,Lea T Grinberg,Jason E Gestwicki,Manuel D Leonetti,Martin Kampmann

doi:10.1074/jbc.ra119.009432

Abstract

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.

Highlights

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)
Using our CRISPR interference (CRISPRi)-based genetic screening platform in a cell-based model of prion-like propagation of tau aggregation, we found that defects in the endosomal sorting complexes required for transport (ESCRT) machinery compromise the integrity of the endolysosomal pathway and thereby promote endolysosomal escape of tau seeds and accelerated propagation of tau aggregation
Our observations were made in a cell-based model, it is intriguing to speculate that they are relevant for propagation of tau aggregation in the context of neurodegenerative diseases

Summary

Introduction

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). We lack a systematic understanding of the cellular pathways controlling prion-like propagation of aggregation. Of Biochemistry and to pools of cytoplasmic tau Together, these findings suggest that endolysosomal escape is a critical step in tau propagation in neurodegenerative diseases. A major breakthrough was the discovery that scrapie, an infectious neurodegenerative disease, is caused by the cell-to-cell propagation of protein aggregates via “prion” forms of the protein [1]. Findings from numerous, independent studies support the hypothesis that prion-like propagation underlies common, noninfectious neurodegenerative diseases, such as Alzheimer’s disease (AD) (recently reviewed in Ref. 2). A systematic understanding of these mechanisms is important, both for the development of therapeutics and for furthering our understanding of why specific neuronal subtypes and brain regions are especially susceptible to specific diseases

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