title: Tau proteins harboring neurodegeneration-linked mutations impair kinesin translocation in vitro.
abstract: We tested the hypothesis that mutant tau proteins that cause neurodegeneration and dementia differentially alter kinesin translocation along microtubules (MTs) relative to normal tau in vitro. We employed complementary in vitro motility assays using purified recombinant kinesin, purified recombinant tau, and purified bovine brain α:β tubulin to isolate interactions among these components without any contribution by cellular regulatory mechanisms. We found that kinesin translocates slower along MTs assembled by any of three independent tau mutants (4-repeat P301L tau, 4-repeat ΔN296 tau, and 4-repeat R406W tau) relative to its translocation rate along MTs assembled by normal, 4-repeat wild type (WT) tau. Moreover, the R406W mutation exhibited isoform specific effects; while kinesin translocation along 4-repeat R406W tau assembled MTs is slower than along MTs assembled by 4-repeat WT tau, the R406W mutation had no effect in the 3-repeat tau context. These data provide strong support for the notion that aberrant modulation of kinesin translocation is a component of tau-mediated neuronal cell death and dementia. Finally, we showed that assembling MTs with taxol before coating them with mutant tau obscured effects of the mutant tau that were readily apparent using more physiologically relevant MTs assembled with tau alone, raising important issues regarding the use of taxol as an experimental reagent and novel insights into therapeutic mechanisms of taxol action.
authors.affiliation: Department of Materials, University of California, Santa Barbara, CA, USA.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Yu
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, USA Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: Nichole E
authors.initials: NE
authors.lastname: LaPointe
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, USA Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: Elmer
authors.initials: E
authors.lastname: Guzman
authors.affiliation: College of Creative Studies, University of California, Santa Barbara, CA, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Pessino
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, USA Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, USA Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, USA Department of Mechanical Engineering, University of California, Santa Barbara, CA, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Valentine
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D045663:Quantum Dots; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D014404:Tubulin; D050257:Tubulin Modulators; D016875:tau Proteins; D016547:Kinesins; D017239:Paclitaxel
keywords: Axonal transport; corticobasal degeneration; frontotemporal dementia with parkinsonism-17; kinesin; microtubules; motility; progressive supranuclear palsy; tau