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

J. Biol. Chem., Vol. 278, Issue 35, 33298-33304, August 29, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/35/33298    most recent M305207200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Makrides, V. Articles by Feinstein, S. C. Search for Related Content PubMed PubMed Citation Articles by Makrides, V. Articles by Feinstein, S. C. Social Bookmarking                      What's this?

Microtubule-dependent Oligomerization of Tau

IMPLICATIONS FOR PHYSIOLOGICAL TAU FUNCTION AND TAUOPATHIES^*

Victoria Makrides  , Ting E. Shen , Rajinder Bhatia , Bettye L. Smith , Julian Thimm , Ratneshwar Lal  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 accumulation of abnormal tau filaments is a pathological hallmark of many neurodegenerative diseases. In 1998, genetic analyses revealed a direct linkage between structural and regulatory mutations in the tau gene and the neurodegenerative disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Importantly, the FTDP-17 phenotype is transmitted in a dominant rather than a recessive manner. However, the underlying molecular mechanisms causing disease remain uncertain. The most common molecular mechanism generating dominant phenotypes is the loss of function of a multimeric complex containing both mutant and wild-type subunits. Therefore, we sought to determine whether tau might normally function as a multimer. We co-incubated ³⁵S-radiolabeled tau and biotinylated tau with taxol stabilized microtubules, at very low molar ratios of tau to tubulin. Subsequent covalent cross-linking followed by affinity-precipitation of the biotinylated tau revealed the formation of microtubule-dependent tau oligomers. We next used atomic force microscopy to independently assess this conclusion. Our results are consistent with the hypothesis that tau forms oligomers upon binding to microtubules. In addition to providing insights into normal tau action, our findings lead us to propose that one mechanism by which mutations in tau may cause cell death is through the formation of tau complexes containing mutant tau molecules in association with wild-type tau. These wild-type-mutant tau complexes may possess altered biological and/or biophysical properties that promote onset of the FTDP-17 phenotype, including neuronal cell death by either altering normal tau-mediated regulation of microtubule-dependent cellular functions and/or promoting the formation of pathological tau aggregates.

Received for publication, May 18, 2003

^* This work was supported by United States Public Health Service Grants NS35010 (to S. C. F.) and GM056290 (to R. L.) and by the California Department of Health Services, Alzheimer's Disease Program (to R. L.). 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.

^¶ To whom correspondence should be addressed: Neuroscience Research Inst. and Dept. of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106. Tel./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:

				A. Deshpande, K. M. Win, and J. Busciglio Tau isoform expression and regulation in human cortical neurons FASEB J, July 1, 2008; 22(7): 2357 - 2367. [Abstract] [Full Text] [PDF]

				K. J. Rosenberg, J. L. Ross, H. E. Feinstein, S. C. Feinstein, and J. Israelachvili Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis PNAS, May 27, 2008; 105(21): 7445 - 7450. [Abstract] [Full Text] [PDF]

				E. E. Congdon, S. Kim, J. Bonchak, T. Songrug, A. Matzavinos, and J. Kuret Nucleation-dependent Tau Filament Formation: THE IMPORTANCE OF DIMERIZATION AND AN ESTIMATION OF ELEMENTARY RATE CONSTANTS J. Biol. Chem., May 16, 2008; 283(20): 13806 - 13816. [Abstract] [Full Text] [PDF]

				H. N. Dawson, V. Cantillana, L. Chen, and M. P. Vitek The Tau N279K Exon 10 Splicing Mutation Recapitulates Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Tauopathy in a Mouse Model J. Neurosci., August 22, 2007; 27(34): 9155 - 9168. [Abstract] [Full Text] [PDF]

				A. I. Iliev, S. Ganesan, G. Bunt, and F. S. Wouters Removal of Pattern-breaking Sequences in Microtubule Binding Repeats Produces Instantaneous Tau Aggregation and Toxicity J. Biol. Chem., December 1, 2006; 281(48): 37195 - 37204. [Abstract] [Full Text] [PDF]

				A. Kar, N. Havlioglu, W.-Y. Tarn, and J. Y. Wu RBM4 Interacts with an Intronic Element and Stimulates Tau Exon 10 Inclusion J. Biol. Chem., August 25, 2006; 281(34): 24479 - 24488. [Abstract] [Full Text] [PDF]

				H. Ding, T. A. Matthews, and G. V. W. Johnson Site-specific Phosphorylation and Caspase Cleavage Differentially Impact Tau-Microtubule Interactions and Tau Aggregation J. Biol. Chem., July 14, 2006; 281(28): 19107 - 19114. [Abstract] [Full Text] [PDF]

				S. F. Levy, A. C. LeBoeuf, M. R. Massie, M. A. Jordan, L. Wilson, and S. C. Feinstein Three- and Four-repeat Tau Regulate the Dynamic Instability of Two Distinct Microtubule Subpopulations in Qualitatively Different Manners: IMPLICATIONS FOR NEURODEGENERATION J. Biol. Chem., April 8, 2005; 280(14): 13520 - 13528. [Abstract] [Full Text] [PDF]

				J. L. Ross, C. D. Santangelo, V. Makrides, and D. K. Fygenson Tau induces cooperative Taxol binding to microtubules PNAS, August 31, 2004; 101(35): 12910 - 12915. [Abstract] [Full Text] [PDF]

				C. Nakao, T. J. Itoh, H. Hotani, and N. Mori Modulation of the Stathmin-like Microtubule Destabilizing Activity of RB3, a Neuron-specific Member of the SCG10 Family, by Its N-terminal Domain J. Biol. Chem., May 28, 2004; 279(22): 23014 - 23021. [Abstract] [Full Text] [PDF]

				M. Eguchi, M. Eguchi-Ishimae, and M. Greaves The small oligomerization domain of gephyrin converts MLL to an oncogene Blood, May 15, 2004; 103(10): 3876 - 3882. [Abstract] [Full Text] [PDF]

				V. Makrides, M. R. Massie, S. C. Feinstein, and J. Lew Evidence for two distinct binding sites for tau on microtubules PNAS, April 27, 2004; 101(17): 6746 - 6751. [Abstract] [Full Text] [PDF]