Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease

Bahareh Eftekharzadeh; J. Gavin Daigle; Larisa E. Kapinos; Alyssa Coyne; Julia Schiantarelli; Yari Carlomagno; Casey Cook; Sean J. Miller; Simon Dujardin; Ana S. Amaral; Jonathan C. Grima; Rachel E. Bennett; Katharina Tepper; Michael DeTure; Charles R. Vanderburgh; Bianca T. Corjuc; Sarah L. DeVos; Jose Antonio Gonzalez; Jeannie Chew; Svetlana Vidensky; Fred H. Gage; Jerome Mertens; Juan Troncoso; Eckhard Mandelkow; Xavier Salvatella; Roderick Y.H. Lim; Leonard Petrucelli; Susanne Wegmann; Jeffrey D. Rothstein; Bradley T. Hyman

doi:10.1016/j.neuron.2018.07.039

Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease

Bahareh Eftekharzadeh, J. Gavin Daigle, Larisa E. Kapinos, Alyssa Coyne, Julia Schiantarelli, Yari Carlomagno, Casey Cook, Sean J. Miller, Simon Dujardin, Ana S. Amaral, Jonathan C. Grima, Rachel E. Bennett, Katharina Tepper, Michael DeTure, Charles R. Vanderburgh, Bianca T. Corjuc, Sarah L. DeVos, Jose Antonio Gonzalez, Jeannie Chew, Svetlana VidenskyFred H. Gage, Jerome Mertens, Juan Troncoso, Eckhard Mandelkow, Xavier Salvatella, Roderick Y.H. Lim, Leonard Petrucelli, Susanne Wegmann, Jeffrey D. Rothstein, Bradley T. Hyman

School of Medicine

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

Abstract

Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies. Nuclear pore complexes control trafficking of proteins and RNA in and out of the nucleus. These studies now provide evidence that AD-related tau disrupts nuclear pore function in Alzheimer's disease and that nuclear pore proteins cause tau to aggregate.

Original language	English (US)
Pages (from-to)	925-940.e7
Journal	Neuron
Volume	99
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2018.07.039
State	Published - Sep 5 2018

Keywords

Alzheimer's disease
Nup98
nuclear pore complex
nucleocytoplasmic transport
tauopathies

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2018.07.039

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Eftekharzadeh, B., Daigle, J. G., Kapinos, L. E., Coyne, A., Schiantarelli, J., Carlomagno, Y., Cook, C., Miller, S. J., Dujardin, S., Amaral, A. S., Grima, J. C., Bennett, R. E., Tepper, K., DeTure, M., Vanderburgh, C. R., Corjuc, B. T., DeVos, S. L., Gonzalez, J. A., Chew, J., ... Hyman, B. T. (2018). Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron, 99(5), 925-940.e7. https://doi.org/10.1016/j.neuron.2018.07.039

Eftekharzadeh, B, Daigle, JG, Kapinos, LE, Coyne, A, Schiantarelli, J, Carlomagno, Y, Cook, C, Miller, SJ, Dujardin, S, Amaral, AS, Grima, JC, Bennett, RE, Tepper, K, DeTure, M, Vanderburgh, CR, Corjuc, BT, DeVos, SL, Gonzalez, JA, Chew, J, Vidensky, S, Gage, FH, Mertens, J, Troncoso, J, Mandelkow, E, Salvatella, X, Lim, RYH, Petrucelli, L, Wegmann, S, Rothstein, JD & Hyman, BT 2018, 'Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease', Neuron, vol. 99, no. 5, pp. 925-940.e7. https://doi.org/10.1016/j.neuron.2018.07.039

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title = "Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease",

abstract = "Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies. Nuclear pore complexes control trafficking of proteins and RNA in and out of the nucleus. These studies now provide evidence that AD-related tau disrupts nuclear pore function in Alzheimer's disease and that nuclear pore proteins cause tau to aggregate.",

keywords = "Alzheimer's disease, Nup98, nuclear pore complex, nucleocytoplasmic transport, tauopathies",

author = "Bahareh Eftekharzadeh and Daigle, {J. Gavin} and Kapinos, {Larisa E.} and Alyssa Coyne and Julia Schiantarelli and Yari Carlomagno and Casey Cook and Miller, {Sean J.} and Simon Dujardin and Amaral, {Ana S.} and Grima, {Jonathan C.} and Bennett, {Rachel E.} and Katharina Tepper and Michael DeTure and Vanderburgh, {Charles R.} and Corjuc, {Bianca T.} and DeVos, {Sarah L.} and Gonzalez, {Jose Antonio} and Jeannie Chew and Svetlana Vidensky and Gage, {Fred H.} and Jerome Mertens and Juan Troncoso and Eckhard Mandelkow and Xavier Salvatella and Lim, {Roderick Y.H.} and Leonard Petrucelli and Susanne Wegmann and Rothstein, {Jeffrey D.} and Hyman, {Bradley T.}",

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doi = "10.1016/j.neuron.2018.07.039",

language = "English (US)",

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AU - Eftekharzadeh, Bahareh

AU - Daigle, J. Gavin

AU - Kapinos, Larisa E.

AU - Coyne, Alyssa

AU - Schiantarelli, Julia

AU - Carlomagno, Yari

AU - Cook, Casey

AU - Miller, Sean J.

AU - Dujardin, Simon

AU - Amaral, Ana S.

AU - Grima, Jonathan C.

AU - Bennett, Rachel E.

AU - Tepper, Katharina

AU - DeTure, Michael

AU - Vanderburgh, Charles R.

AU - Corjuc, Bianca T.

AU - DeVos, Sarah L.

AU - Gonzalez, Jose Antonio

AU - Chew, Jeannie

AU - Vidensky, Svetlana

AU - Gage, Fred H.

AU - Mertens, Jerome

AU - Troncoso, Juan

AU - Mandelkow, Eckhard

AU - Salvatella, Xavier

AU - Lim, Roderick Y.H.

AU - Petrucelli, Leonard

AU - Wegmann, Susanne

AU - Rothstein, Jeffrey D.

AU - Hyman, Bradley T.

PY - 2018/9/5

Y1 - 2018/9/5

N2 - Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies. Nuclear pore complexes control trafficking of proteins and RNA in and out of the nucleus. These studies now provide evidence that AD-related tau disrupts nuclear pore function in Alzheimer's disease and that nuclear pore proteins cause tau to aggregate.

AB - Tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD), but the mechanism underlying tau-associated neural damage remains unclear. Here, we show that tau can directly interact with nucleoporins of the nuclear pore complex (NPC) and affect their structural and functional integrity. Pathological tau impairs nuclear import and export in tau-overexpressing transgenic mice and in human AD brain tissue. Furthermore, the nucleoporin Nup98 accumulates in the cell bodies of some tangle-bearing neurons and can facilitate tau aggregation in vitro. These data support the hypothesis that tau can directly interact with NPC components, leading to their mislocalization and consequent disruption of NPC function. This raises the possibility that NPC dysfunction contributes to tau-induced neurotoxicity in AD and tauopathies. Nuclear pore complexes control trafficking of proteins and RNA in and out of the nucleus. These studies now provide evidence that AD-related tau disrupts nuclear pore function in Alzheimer's disease and that nuclear pore proteins cause tau to aggregate.

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KW - Nup98

KW - nuclear pore complex

KW - nucleocytoplasmic transport

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JO - Neuron

JF - Neuron

IS - 5

ER -

Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease

Abstract

Keywords

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