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Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s Disease

2018; Cell Press; Volume: 99; Issue: 5 Linguagem: Inglês

10.1016/j.neuron.2018.07.039

1097-4199

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

Trace Elements in Health

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.