title: Microtubule-dependent oligomerization of tau. Implications for physiological tau function and tauopathies.
abstract: 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.
authors.affiliation: Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California 93106, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Makrides
authors.forename: Ting E
authors.initials: TE
authors.lastname: Shen
authors.forename: Rajinder
authors.initials: R
authors.lastname: Bhatia
authors.forename: Bettye L
authors.initials: BL
authors.lastname: Smith
authors.forename: Julian
authors.initials: J
authors.lastname: Thimm
authors.forename: Ratneshwar
authors.initials: R
authors.lastname: Lal
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
mesh_terms: D000818:Animals; D001710:Biotin / Q000737:chemistry; D019921:Biotinylation; D016923:Cell Death; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003704:Dementia / Q000235:genetics; D019281:Dimerization; D005022:Ethyldimethylaminopropyl Carbodiimide / Q000494:pharmacology; D018625:Microscopy, Atomic Force; D008870:Microtubules / Q000737:chemistry* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051381:Rats; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D003432:Cross-Linking Reagents; D016875:tau Proteins; D001710:Biotin; D005022:Ethyldimethylaminopropyl Carbodiimide