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J. Biol. Chem., Vol. 280, Issue 14, 13520-13528, April 8, 2005

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Three- and Four-repeat Tau Regulate the Dynamic Instability of Two Distinct Microtubule Subpopulations in Qualitatively Different Manners

IMPLICATIONS FOR NEURODEGENERATION^*

Sasha F. Levy, Adria C. LeBoeuf, Michelle R. Massie, Mary Ann Jordan, Leslie Wilson, and Stuart C. Feinstein

From the Neuroscience Research Institute and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106

The microtubule-associated protein tau is implicated in the pathogenesis of many neurodegenerative diseases, including fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), in which both RNA splicing and amino acid substitution mutations in tau cause dominantly inherited early onset dementia. RNA-splicing FTDP-17 mutations alter the wild-type 50:50 3-repeat (3R) to 4-repeat (4R) tau isoform ratio, usually resulting in an excess of 4R tau. To examine further how splicing mutations might cause dysfunction by misregulation of microtubule dynamics, we used video microscopy to determine the in vitro behavior of individual microtubules stabilized by varying amounts of human 4R and 3R tau. At low tau:tubulin ratios (1:55 and 1:45), all 3R isoforms reduced microtubule growth rates relative to the no-tau control, whereas all 4R isoforms increased them; however, at a high tau:tubulin ratio (1:20), both 4R and 3R tau increased the growth rates. Further analysis revealed two distinct subpopulations of growing microtubules in the absence of tau. Increasing concentrations of both 4R and 3R tau resulted in an increase in the size of the faster growing subpopulation of microtubules; however, 4R tau caused a redistribution to the faster growing subpopulation at lower tau:tubulin ratios than 3R tau. This modulation of discrete growth rate subpopulations by tau suggests that tau causes a conformational shift in the microtubule resulting in altered dynamics. Quantitative and qualitative differences observed between 4R and 3R tau are consistent with a "microtubule misregulation" model in which abnormal tau isoform expression results in the inability to properly regulate microtubule dynamics, leading to neuronal death and dementia.

Received for publication, November 30, 2004 , and in revised form, January 21, 2005.

^* This work was supported by National Institutes of Health Grants NS35010 (to S. C. F), NS13560 (to L. W.), and CA57291 (to M. A. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Neuroscience Research Institute, Bldg. 571, Rm. 6129, University of California, Santa Barbara, CA 93106. Tel.: 805-893-2659; Fax: 805-893-2659; E-mail: feinstei{at}lifesci.ucsb.edu.

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