Faculty

The presence of abnormal deposits of filamentous tau is thought to be a major part of the neurodegenerative process. For example, the location and amounts of tau pathology in specific regions of the brain correlates with the type and degree of observed dementia in patients. In addition, several mutations in the tau gene have been shown to be directly linked to increased tau pathology and neurodegeneration in familial cases of frontotemporal dementia.

TTau is a microtubule-associated protein that was originally discovered to associate with microtubules and provide stabilization for these structures. However, in the late 1980's, it was discovered that a "hyperphosphorylated" form of tau was the major component of several pathological structures in Alzheimer's disease known as neuropil threads, neurofibrillary tangles, and neuritic plaques. Further characterization of these structures revealed that the tau present in these structures had self-associated into filamentous structures known as straight filaments and paired-helical filaments. Since that time, numerous diseases have been identified as having significant tau pathology such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration.

The major goal of this laboratory is to understand the molecular mechanisms that lead to the polymerization of the microtubule-associated protein tau into pathological structures observed in Alzheimer's disease and other neurodegenerative disorders. The main thrust of research will involve the detailed investigation of the effects of tau phosphorylation on its ability to polymerize, bind microtubules, and stabilize microtubules. This research will be accomplished using several molecular biology and biochemical approaches, including site-directed mutagenesis, laser light scattering, electron microscopy, and in vitro binding assays.

Representative Publications

Carlson, S.W., Branden, M., Voss, K., Sun, Q., Rankin, C.A., and Gamblin, T. C (2007)

"A complex mechanism for inducer mediated tau polymerization" Biochemistry 46, 8838-8849.

Rankin, C. A., Sun, Q., and Gamblin, T. C. (2007)

"Tau phosphorylation by GSK3 promotes tangled filament morphology" Molecular Neurodegeneration 2:12

Sarthy, J.F, and Gamblin, T.C. (2006)

"A light scattering assay for arachidonic acid induced tau fibrillization without interfering micellization". Analytical Biochemistry, 353(1):150-2.

Rankin, C.A., Sun, Q., and Gamblin, T.C. (2005)

"Pseudo-phosphorylation of tau at Ser 202 and Thr 205 affects tau filament formation". Brain Res Mol Brain Res. 138: 84-93.

Gamblin, TC (2005)

"Potential structure/function relationships of predicted secondary structural elements of tau. Biochim Biophys Acta". 1739(2-3): 140-9

Gamblin, T.C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A.L., Lu, M., Fu, Y., Garcia-Sierra, F., LaPointe, N., Miller, R., Berry, R.W., Binder, L.I., and Cryns, V.L.. (2003)

Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A. 100(17):10032-7.

Gamblin, T.C., Berry, R.W., and Binder, L.I. (2003)

Tau polymerization: role of the amino terminus. Biochemistry 42(7):2252-7.

Gamblin, T.C., Berry, R.W., and Binder, L.I. (2003)

“Modeling tau polymerization in vitro: a review and synthesis” Biochemistry 42:15009-17.

Gamblin, T. C., King, M. E., Kuret, J., Berry, R. W., and Binder, L. I. (2000)

Oxidative Regulation of Fatty Acid-Induced Tau Polymerization. Biochemistry 39: 14203-14210.

Abraha, A., Ghoshal, N., Gamblin, T. C., Cryns, V., Berry, R. W., Kuret, J., and Binder, L. I. (2000)

C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease. J. Cell Science 113: 3737-3745.

Gamblin, T. C., King, M. E., Dawson, H., Vitek, M. P., Kuret, J., Berry, R. W., and Binder, L. I. (2000)

In Vitro Polymerization of Tau Protein Monitored by Laser Light Scattering: Method and Application to the Study of FTDP-17 Mutants. Biochemistry 39: 6136-6144.

King, M. E., Gamblin, T. C., Kuret, J., and Binder, L. I. (2000)

Differential assembly of human tau isoforms in the presence of arachidonic acid. J. Neurochemistry 74: 1749-57.