HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 17, 11856-11863, April 28, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/17/11856    most recent M509420200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bunker, J. M. Articles by Feinstein, S. C. Search for Related Content PubMed PubMed Citation Articles by Bunker, J. M. Articles by Feinstein, S. C. Social Bookmarking                      What's this?

FTDP-17 Mutations Compromise the Ability of Tau to Regulate Microtubule Dynamics in Cells^*

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

The neural microtubule-associated protein Tau binds directly to microtubules and regulates their dynamic behavior. In addition to being required for normal development, maintenance, and function of the nervous system, Tau is associated with several neurodegenerative diseases, including Alzheimer disease. One group of neurodegenerative dementias known as FTDP-17 (fronto-temporal dementia with Parkinsonism linked to chromosome 17) is directly linked genetically to mutations in the tau gene, demonstrating that Tau misfunction can cause neuronal cell death and dementia. These mutations result either in amino acid substitutions in Tau or in altered Tau mRNA splicing that skews the expression ratio of wild-type 3-repeat and 4-repeat Tau isoforms. Because wild-type Tau regulates microtubule dynamics, one possible mechanism underlying Tau-mediated neurodegeneration is aberrant regulation of microtubule behavior. In this study, we microinjected normal and mutated Tau protein into cultured cells expressing fluorescent tubulin and measured the effects on the dynamic instability of individual microtubules. We found that the FTDP-17 amino acid substitutions G272V (in both 3-repeat and 4-repeat Tau contexts), K280, and P301L all exhibited markedly reduced abilities to regulate dynamic instability relative to wild-type Tau. In contrast, the FTDP-17 R406W mutation (which maps in a regulatory region outside the microtubule binding domain of Tau) did not significantly alter the ability of 3-repeat or 4-repeat Tau to regulate microtubule dynamics. Overall, these data are consistent with a loss-of-function model in which both amino acid substitutions and altered mRNA splicing in Tau lead to neurodegeneration by diminishing the ability of Tau to properly regulate microtubule dynamics.

Received for publication, August 25, 2005 , and in revised form, February 21, 2006.

^* 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.) and Information Technology Research Grant 0331697 from the National Science Foundation (to S. C. F. and L. W.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Movies1-3.

¹ 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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. Yotsumoto, T. Saito, A. Asada, T. Oikawa, T. Kimura, C. Uchida, K. Ishiguro, T. Uchida, M. Hasegawa, and S.-i. Hisanaga Effect of Pin1 or Microtubule Binding on Dephosphorylation of FTDP-17 Mutant Tau J. Biol. Chem., June 19, 2009; 284(25): 16840 - 16847. [Abstract] [Full Text] [PDF]

				A. C. LeBoeuf, S. F. Levy, M. Gaylord, A. Bhattacharya, A. K. Singh, M. A. Jordan, L. Wilson, and S. C. Feinstein FTDP-17 Mutations in Tau Alter the Regulation of Microtubule Dynamics: AN "ALTERNATIVE CORE" MODEL FOR NORMAL AND PATHOLOGICAL TAU ACTION J. Biol. Chem., December 26, 2008; 283(52): 36406 - 36415. [Abstract] [Full Text] [PDF]

				T. Vandebroek, D. Terwel, T. Vanhelmont, M. Gysemans, C. Van Haesendonck, Y. Engelborghs, J. Winderickx, and F. Van Leuven Microtubule Binding and Clustering of Human Tau-4R and Tau-P301L Proteins Isolated from Yeast Deficient in Orthologues of Glycogen Synthase Kinase-3beta or cdk5 J. Biol. Chem., September 1, 2006; 281(35): 25388 - 25397. [Abstract] [Full Text] [PDF]