The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity
LaPointe, Nichole E.
Morfini, Gerardo A.
Pigino, Gustavo F.
Gaisina, Irina N.
Kozikowski, Alan P.
Binder, Lester I.
Brady, Scott T.
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The neuropathology of Alzheimer’s disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dyneindependent FAT rates evaluated by video microscopy. While perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in Journal of Neuroscience Research 87 (2009): 440-451, doi:10.1002/jnr.21850.
Suggested CitationPreprint: LaPointe, Nichole E., Morfini, Gerardo A., Pigino, Gustavo F., Gaisina, Irina N., Kozikowski, Alan P., Binder, Lester I., Brady, Scott T., "The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity", 2008-04, https://doi.org/10.1002/jnr.21850, https://hdl.handle.net/1912/2756
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