title: The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity.
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 dynein-dependent 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.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Nichole E
authors.initials: NE
authors.lastname: LaPointe
authors.forename: Gerardo
authors.initials: G
authors.lastname: Morfini
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pigino
authors.forename: Irina N
authors.initials: IN
authors.lastname: Gaisina
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Lester I
authors.initials: LI
authors.lastname: Binder
authors.forename: Scott T
authors.initials: ST
authors.lastname: Brady
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D049832:Decapodiformes; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D016547:Kinesins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; D054645:Protein Phosphatase 1; D016547:Kinesins
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