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Cell Rep. 2018 May 15;23(7):2039-2055. doi: 10.1016/j.celrep.2018.04.056.

Unconventional Secretion Mediates the Trans-cellular Spreading of Tau.

Author information

1
Schaller Research Group at the University of Heidelberg and the DKFZ, Proteostasis in Neurodegenerative Disease (B180), INF 581, 69120 Heidelberg, Germany; Heidelberg University Biochemistry Center (BZH), INF 328, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, INF 234, 69120 Heidelberg, Germany.
2
Heidelberg University Biochemistry Center (BZH), INF 328, 69120 Heidelberg, Germany.
3
Schaller Research Group at the University of Heidelberg and the DKFZ, Proteostasis in Neurodegenerative Disease (B180), INF 581, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Center for Molecular Biology of Heidelberg University (ZMBH), INF 282, 69120 Heidelberg, Germany.
4
Heidelberg University Biochemistry Center (BZH), INF 328, 69120 Heidelberg, Germany. Electronic address: walter.nickel@bzh.uni-heidelberg.de.
5
Schaller Research Group at the University of Heidelberg and the DKFZ, Proteostasis in Neurodegenerative Disease (B180), INF 581, 69120 Heidelberg, Germany. Electronic address: thomas.r.jahn@abbvie.com.

Abstract

The progressive deposition of misfolded hyperphosphorylated tau is a pathological hallmark of tauopathies, including Alzheimer's disease. However, the underlying molecular mechanisms governing the intercellular spreading of tau species remain elusive. Here, we show that full-length soluble tau is unconventionally secreted by direct translocation across the plasma membrane. Increased secretion is favored by tau hyperphosphorylation, which provokes microtubule detachment and increases the availability of free protein inside cells. Using a series of binding assays, we show that free tau interacts with components enriched at the inner leaflet of the plasma membrane, finally leading to its translocation across the plasma membrane mediated by sulfated proteoglycans. We provide further evidence that secreted soluble tau species spread trans-cellularly and are sufficient for the induction of intracellular tau aggregation in adjacent cells. Our study demonstrates the mechanistic details of tau secretion and provides insights into the initiation and progression of tau pathology.

KEYWORDS:

Alzheimer’s disease; hyperphosphorylation; tau aggregation; tau protein; trans-cellular spreading; unconventional secretion

PMID:
29768203
DOI:
10.1016/j.celrep.2018.04.056
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