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Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s Disease

66 Pages Posted: 6 Apr 2018 Sneak Peek Status: Review Complete

See all articles by Bahareh Eftekharzadeh

Bahareh Eftekharzadeh

Harvard University - Department of Neurology

J. Gavin Daigle

Johns Hopkins University - Brain Science Institute

Larisa E. Kapinos

Catalan Institution of Research and Advanced Studies (ICREA)

Simon Dujardin

Harvard University - Department of Neurology

Alyssa Coyne

Johns Hopkins University - Brain Science Institute

Sean J. Miller

Johns Hopkins University - Brain Science Institute

Casey Cook

Mayo Clinic - Florida - Department of Neuroscience

Jonathan C. Grima

Johns Hopkins University - Brain Science Institute

Rachel E. Bennett

Harvard University - Department of Neurology

Julia Schiantarelli

Harvard University - Department of Neurology

Yari Carlomagno

Mayo Clinic - Florida - Department of Neuroscience

Katharina Tepper

Harvard University - Department of Neurology

Ana C. Amaral

Harvard University - Department of Neurology

Sarah L. DeVos

Harvard University - Department of Neurology

Charles R. Vanderburgh

Harvard University - Department of Neurology

Masato Maesako

Harvard University - Department of Neurology

Caitlin Commins

Harvard University - Department of Neurology

Bianca T. Corjuc

Harvard University - Department of Neurology

Jose Antonio Gonzalez

Harvard University - Department of Neurology

Jerome Mertens

Salk Institute for Biological Studies - Laboratory of Genetics

Danny Mackenzie

Harvard University - Department of Neurology

Svetlana Vidensky

Johns Hopkins University - Brain Science Institute

Nicholas J. Valle

Johns Hopkins University - Brain Science Institute

Uzma Hussain

Johns Hopkins University - Brain Science Institute

Fred H. Gage

Salk Institute for Biological Studies - Laboratory of Genetics

Juan Troncoso

Johns Hopkins University - Department of Pathology

Xavier Salvatella

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Roderick Y. H. Lim

University of Basel - Biozentrum

Eckhard Mandelkow

German Center for Neurodegenerative Diseases (DZNE)

Susanne Wegmann

Harvard University - Department of Neurology

Leonard Petrucelli

Mayo Clinic - Florida - Department of Neuroscience

Jeffrey D. Rothstein

Johns Hopkins University - Brain Science Institute

Bradley T. Hyman

Harvard University - Department of Neurology

More...

Abstract

Tau protein, which normally functions to stabilize microtubules, is the major constituent of neurofibrillary tangles in Alzheimer’s disease (AD). The mechanism underlying tau-associated neural damage remains unclear. We now show that tau can interact with nuclear pore complex (NPC) constituents and affect their structural and functional integrity. Pathological tau leads to dissociation of nuclear pore complex proteins, and impairs nuclear export and import in vitro, in tau overexpressing transgenic mouse models, and in human AD tissue. Moreover, a nuclear pore component, Nup98, surprisingly colocalizes with neurofibrillary tangles in neuronal soma, and both in vivo and in vitro directly interacts with tau to greatly facilitate its aggregation. These data support the hypothesis that tau directly interacts with nuclear pore complex constituents, leading to their mislocalization and to disruption of nuclear pore function, raising the possibility that nuclear pore dysfunction contributes to tau-induced neurotoxicity in Alzheimer’s disease.

Suggested Citation

Eftekharzadeh, Bahareh and Daigle, J. Gavin and Kapinos, Larisa E. and Dujardin, Simon and Coyne, Alyssa and Miller, Sean J. and Cook, Casey and Grima, Jonathan C. and Bennett, Rachel E. and Schiantarelli, Julia and Carlomagno, Yari and Tepper, Katharina and Amaral, Ana C. and DeVos, Sarah L. and Vanderburgh, Charles R. and Maesako, Masato and Commins, Caitlin and Corjuc, Bianca T. and Gonzalez, Jose Antonio and Mertens, Jerome and Mackenzie, Danny and Vidensky, Svetlana and Valle, Nicholas J. and Hussain, Uzma and Gage, Fred H. and Troncoso, Juan and Salvatella, Xavier and Lim, Roderick Y. H. and Mandelkow, Eckhard and Wegmann, Susanne and Petrucelli, Leonard and Rothstein, Jeffrey D. and Hyman, Bradley T., Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s Disease (2018). Available at SSRN: https://ssrn.com/abstract=3155576 or http://dx.doi.org/10.2139/ssrn.3155576
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Bahareh Eftekharzadeh

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

J. Gavin Daigle

Johns Hopkins University - Brain Science Institute

Baltimore, MD 21205
United States

Larisa E. Kapinos

Catalan Institution of Research and Advanced Studies (ICREA)

Passeig Lluís Companys, 23
Barcelona, 08010
Spain

Simon Dujardin

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Alyssa Coyne

Johns Hopkins University - Brain Science Institute

Baltimore, MD 21205
United States

Sean J. Miller

Johns Hopkins University - Brain Science Institute

Baltimore, MD 21205
United States

Casey Cook

Mayo Clinic - Florida - Department of Neuroscience

4500 San Pablo Rd S
Jacksonville, FL 32224
United States

Jonathan C. Grima

Johns Hopkins University - Brain Science Institute

Baltimore, MD 21205
United States

Rachel E. Bennett

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Julia Schiantarelli

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Yari Carlomagno

Mayo Clinic - Florida - Department of Neuroscience

4500 San Pablo Rd S
Jacksonville, FL 32224
United States

Katharina Tepper

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Ana C. Amaral

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Sarah L. DeVos

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Charles R. Vanderburgh

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Masato Maesako

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Caitlin Commins

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Bianca T. Corjuc

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Jose Antonio Gonzalez

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Jerome Mertens

Salk Institute for Biological Studies - Laboratory of Genetics

10010 North Torrey Pines Road
La Jolla, CA 92037-100
United States

Danny Mackenzie

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Svetlana Vidensky

Johns Hopkins University - Brain Science Institute

Baltimore, MD 21205
United States

Nicholas J. Valle

Johns Hopkins University - Brain Science Institute

Baltimore, MD 21205
United States

Uzma Hussain

Johns Hopkins University - Brain Science Institute

Baltimore, MD 21205
United States

Fred H. Gage

Salk Institute for Biological Studies - Laboratory of Genetics

10010 North Torrey Pines Road
La Jolla, CA 92037-100
United States

Juan Troncoso

Johns Hopkins University - Department of Pathology

Baltimore, MD 21231
United States

Xavier Salvatella

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona) ( email )

Baldiri​ ​Reixac​ ​10
Barcelona, 08028
Spain

Roderick Y. H. Lim

University of Basel - Biozentrum

Klingelbergstrasse 50-70
Basel, CH-4056
Switzerland

Eckhard Mandelkow

German Center for Neurodegenerative Diseases (DZNE)

von Siebold Strasse 3a
Goettingen, 37075
Germany

Susanne Wegmann

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

Leonard Petrucelli

Mayo Clinic - Florida - Department of Neuroscience

4500 San Pablo Rd S
Jacksonville, FL 32224
United States

Jeffrey D. Rothstein (Contact Author)

Johns Hopkins University - Brain Science Institute

Baltimore, MD 21205
United States

Bradley T. Hyman

Harvard University - Department of Neurology

Wang Ambulatory Care Center, 8th Floor, Suite 835
Charlestown, MA 02129
United States

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