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Hum Mol Genet. 2019 May 1;28(9):1498-1514. doi: 10.1093/hmg/ddy442.

Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport.

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Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Departments of Molecular Medicine and Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA.
Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal.
German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, Bonn, Germany.
MPI for Neurological Research, Hamburg Outstation, c/o Deutsches Elektronen-Synchrotron, Notkestrasse 85, Hamburg, Germany.
The Center of Advanced European Studies and Research, Ludwig-Erhard-Allee 2, Bonn, Germany.
Department of Physiology, University of California San Francisco, San Francisco, CA, USA.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
The Buck Institute for Research on Aging, Novato, CA, USA.
Department of Physics, University of California San Diego, La Jolla, CA, USA.


Mutations in the microtubule-associated protein tau (MAPT) underlie multiple neurodegenerative disorders, yet the pathophysiological mechanisms are unclear. A novel variant in MAPT resulting in an alanine to threonine substitution at position 152 (A152T tau) has recently been described as a significant risk factor for both frontotemporal lobar degeneration and Alzheimer's disease. Here we use complementary computational, biochemical, molecular, genetic and imaging approaches in Caenorhabditis elegans and mouse models to interrogate the effects of the A152T variant on tau function. In silico analysis suggests that a threonine at position 152 of tau confers a new phosphorylation site. This finding is borne out by mass spectrometric survey of A152T tau phosphorylation in C. elegans and mouse. Optical pulse-chase experiments of Dendra2-tau demonstrate that A152T tau and phosphomimetic A152E tau exhibit increased diffusion kinetics and the ability to traverse across the axon initial segment more efficiently than wild-type (WT) tau. A C. elegans model of tauopathy reveals that A152T and A152E tau confer patterns of developmental toxicity distinct from WT tau, likely due to differential effects on retrograde axonal transport. These data support a role for phosphorylation of the variant threonine in A152T tau toxicity and suggest a mechanism involving impaired retrograde axonal transport contributing to human neurodegenerative disease.

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