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, Vanderburg CR, Corjuc BT, DeVos SL, Gonzalez JA, Chew J, Vidensky S, Gage FH, Mertens J, Troncoso J, Mandelkow E, Salvatella X, Lim RY, Petrucelli L, Wegmann S, Rothstein JD, Hyman BT. Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron. 2018 Sep 5;99(5):925-940.e7. PubMed.

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Comments

  1. Nucleocytoplasmic transport of molecules is essential for normal cell function. It is, in my opinion, the most basic and fundamental processes that initiate a cascade of events that leads to cellular aging and cell death. The mislocalization of molecules has been described in every neurological condition, including cancer, but to date, most of the work has been descriptive. The work done by Rothstein and Hyman nails down a direct mechanism associated with the nucleocytoplasmic dysfunction in Alzheimer’s disease. This is a critical step in developing targeted therapy, either tau-directed or the interaction between Nup98 and tau. Many nucleoporin therapies have already been developed in cancer, and just maybe, we can repurpose cancer drugs targeted to the nuclear transport machinery to restore nucleocytoplasmic homeostasis in Alzheimer’s disease.

    View all comments by Diego Mastroeni

  2. I really liked this study, which elegantly combines work in human and transgenic tissue, in vitro and in primary cultures. The human brain and doxycycline rescue experiments in rTg4510 mice are especially compelling. I think the question (admittedly a difficult one) that remains for all pathological mechanisms that have been identified for tau is, what are their relative contributions to disease initiation and progression? In follow-up work it would be interesting to address whether and how murine and human tau differ in disrupting Nup98 and nucleocytoplamsic transport, and whether there is a role for specific post-translational modifications. Another interesting question is whether there are fundamental differences between primary and secondary tauopathies. Tau remains anything but a dull protein!

    View all comments by Jürgen Götz

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