The amino terminus of tau inhibits kinesin-dependent axonal transport

Implications for filament toxicity

Nichole E. LaPointe, Gerardo Morfini, Gustavo Pigino, Irina N. Gaisina, Alan P. Kozikowski, Lester I. Binder, Scott T. Brady

Research output: Contribution to journalArticle

Abstract

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 were evaluated by video microscopy. Although 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.

Original languageEnglish (US)
Pages (from-to)440-451
Number of pages12
JournalJournal of Neuroscience Research
Volume87
Issue number2
DOIs
StatePublished - Feb 1 2009
Externally publishedYes

Fingerprint

Kinesin
Axonal Transport
Tauopathies
Glycogen Synthase Kinase 3
Protein Phosphatase 1
Video Microscopy
Decapodiformes
Microtubule-Associated Proteins
Microtubules
Polymerization
Amino Acid Sequence
Alzheimer Disease
Protein Isoforms
Perfusion
Pharmacology

Keywords

  • Alzheimer's disease
  • Axonal transport
  • GSK3
  • Kinesin
  • PP1
  • Tau
  • Tau filament

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

LaPointe, N. E., Morfini, G., Pigino, G., Gaisina, I. N., Kozikowski, A. P., Binder, L. I., & Brady, S. T. (2009). The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity. Journal of Neuroscience Research, 87(2), 440-451. https://doi.org/10.1002/jnr.21850

The amino terminus of tau inhibits kinesin-dependent axonal transport : Implications for filament toxicity. / LaPointe, Nichole E.; Morfini, Gerardo; Pigino, Gustavo; Gaisina, Irina N.; Kozikowski, Alan P.; Binder, Lester I.; Brady, Scott T.

In: Journal of Neuroscience Research, Vol. 87, No. 2, 01.02.2009, p. 440-451.

Research output: Contribution to journalArticle

LaPointe, NE, Morfini, G, Pigino, G, Gaisina, IN, Kozikowski, AP, Binder, LI & Brady, ST 2009, 'The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity', Journal of Neuroscience Research, vol. 87, no. 2, pp. 440-451. https://doi.org/10.1002/jnr.21850
LaPointe, Nichole E. ; Morfini, Gerardo ; Pigino, Gustavo ; 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. In: Journal of Neuroscience Research. 2009 ; Vol. 87, No. 2. pp. 440-451.
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