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 C Troncoso, Eckhard Mandelkow, Xavier Salvatella, Roderick Y.H. Lim, Leonard Petrucelli, Susanne Wegmann, Jeffrey D Rothstein, Bradley T. Hyman

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)925-940.e7
JournalNeuron
Volume99
Issue number5
DOIs
StatePublished - Sep 5 2018

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Keywords

  • Alzheimer's disease
  • nuclear pore complex
  • nucleocytoplasmic transport
  • Nup98
  • tauopathies

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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