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PMID: 18798283 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity.

Journal of neuroscience research ·Vol. 87 ·No. 2 ·2009-02-00 ·Pages 440-51

LaPointe NE, Morfini G, Pigino G, Gaisina IN, Kozikowski AP, Binder LI, Brady ST

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.

MeSH Terms
Animals Axonal Transport/physiology Cytoskeleton/metabolism Decapodiformes Glycogen Synthase Kinase 3/metabolism Humans Immunoblotting Kinesins/metabolism Microtubules/metabolism Protein Isoforms/chemistry,metabolism Protein Phosphatase 1/metabolism tau Proteins/chemistry,metabolism,toxicity
Chemicals
Protein Isoforms tau Proteins Glycogen Synthase Kinase 3 Protein Phosphatase 1 Kinesins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
LaPointe Nichole E
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Morfini Gerardo
Pigino Gustavo
Gaisina Irina N
Kozikowski Alan P
Binder Lester I
Brady Scott T
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Article Info
Journal
Journal of neuroscience research
Abbr.
J Neurosci Res
ISSN
1097-4547
DOI
10.1002/jnr.21850
Published
2009-02-00
Pages
440-51
Language
English
Region
United States
NLM ID
7600111
PMCID
PMC2739042
Subset
IM
Grants
NINDS NIH HHS · R01 NS023320-17 · United States
NINDS NIH HHS · R56 NS023868 · United States
NINDS NIH HHS · R01 NS023320 · United States
NINDS NIH HHS · NS43408 · United States
NINDS NIH HHS · R01 NS023868-21 · United States
NINDS NIH HHS · R01 NS041170 · United States
NINDS NIH HHS · NS23320 · United States
NIA NIH HHS · AG14453 · United States
NINDS NIH HHS · NS049834 · United States
NINDS NIH HHS · R01 NS043408 · United States
NINDS NIH HHS · F31 NS049834 · United States
NINDS NIH HHS · NS41170 · United States
NINDS NIH HHS · NS23868 · United States
NIA NIH HHS · R37 AG014453 · United States
NINDS NIH HHS · R01 NS023868 · United States
NINDS NIH HHS · R01 NS041170-06 · United States
External Links
PubMed source DOI: 10.1002/jnr.21850 PMC Full Text View journal details
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