FRMD4A–cytohesin signaling modulates the cellular release of tau

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Sammanfattning

One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein. Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase C. (aPKC.) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.
Originalspråkengelska
TidskriftJournal of Cell Science
Volym129
Utgåva10
Sidor (från-till)2003-2015
Antal sidor13
ISSN0021-9533
DOI
StatusPublicerad - jul 2016
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3112 Neurovetenskaper

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title = "FRMD4A–cytohesin signaling modulates the cellular release of tau",
abstract = "One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein. Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase C. (aPKC.) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.",
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author = "Xu Yan and Nyk{\"a}nen, {Lari Niko-Petteri} and Brunello, {Cecilia Anna} and Annakaisa Haapasalo and Mikko Hiltunen and Uronen, {Riikka-Liisa Eveliina} and Huttunen, {Henri Juhani}",
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FRMD4A–cytohesin signaling modulates the cellular release of tau. / Yan, Xu; Nykänen, Lari Niko-Petteri; Brunello, Cecilia Anna; Haapasalo, Annakaisa; Hiltunen, Mikko; Uronen, Riikka-Liisa Eveliina; Huttunen, Henri Juhani.

I: Journal of Cell Science, Vol. 129, Nr. 10, 07.2016, s. 2003-2015.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

T1 - FRMD4A–cytohesin signaling modulates the cellular release of tau

AU - Yan, Xu

AU - Nykänen, Lari Niko-Petteri

AU - Brunello, Cecilia Anna

AU - Haapasalo, Annakaisa

AU - Hiltunen, Mikko

AU - Uronen, Riikka-Liisa Eveliina

AU - Huttunen, Henri Juhani

PY - 2016/7

Y1 - 2016/7

N2 - One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein. Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase C. (aPKC.) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.

AB - One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein. Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase C. (aPKC.) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.

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