Identification of cis-acting determinants mediating the unconventional secretion of tau

Abstract The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. While recent findings suggest the involvement of unconventional secretory pathways driving...

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Autores principales:	Taxiarchis Katsinelos, William A. McEwan, Thomas R. Jahn, Walter Nickel
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d540ac5e981d4160bd3639f7173fa3e4
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spelling	oai:doaj.org-article:d540ac5e981d4160bd3639f7173fa3e42021-12-02T16:05:55ZIdentification of cis-acting determinants mediating the unconventional secretion of tau10.1038/s41598-021-92433-32045-2322https://doaj.org/article/d540ac5e981d4160bd3639f7173fa3e42021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92433-3https://doaj.org/toc/2045-2322Abstract The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis-elements that are important for both unconventional secretion and trans-cellular propagation of tau.Taxiarchis KatsinelosWilliam A. McEwanThomas R. JahnWalter NickelNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Taxiarchis Katsinelos William A. McEwan Thomas R. Jahn Walter Nickel Identification of cis-acting determinants mediating the unconventional secretion of tau
description	Abstract The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis-elements that are important for both unconventional secretion and trans-cellular propagation of tau.
format	article
author	Taxiarchis Katsinelos William A. McEwan Thomas R. Jahn Walter Nickel
author_facet	Taxiarchis Katsinelos William A. McEwan Thomas R. Jahn Walter Nickel
author_sort	Taxiarchis Katsinelos
title	Identification of cis-acting determinants mediating the unconventional secretion of tau
title_short	Identification of cis-acting determinants mediating the unconventional secretion of tau
title_full	Identification of cis-acting determinants mediating the unconventional secretion of tau
title_fullStr	Identification of cis-acting determinants mediating the unconventional secretion of tau
title_full_unstemmed	Identification of cis-acting determinants mediating the unconventional secretion of tau
title_sort	identification of cis-acting determinants mediating the unconventional secretion of tau
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d540ac5e981d4160bd3639f7173fa3e4
work_keys_str_mv	AT taxiarchiskatsinelos identificationofcisactingdeterminantsmediatingtheunconventionalsecretionoftau AT williamamcewan identificationofcisactingdeterminantsmediatingtheunconventionalsecretionoftau AT thomasrjahn identificationofcisactingdeterminantsmediatingtheunconventionalsecretionoftau AT walternickel identificationofcisactingdeterminantsmediatingtheunconventionalsecretionoftau
_version_	1718385178140737536

Identification of cis-acting determinants mediating the unconventional secretion of tau

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