The microtubule associated protein tau is essential for the development and maintenance of the nervous system. On the other hand, tau hyper-phosphorylation and dysfunction have long been correlated with Alzheimer's disease and a number of related dementias. Recent genetic evidence extended these correlations, demonstrating that mutations affecting either the primary structure of tau or the regulation of tau RNA alternative splicing can cause FTDP-17, a collection of neurodegenerative disorders with many similarities to Alzheimer's disease, including abnormal tau fiber formation, neuronal cell death and dementia. Additional biochemical and genetic data support the conclusion that pathological tau action is likely a key component in Alzheimer's, FTDP-17 and additional """"""""tauopathies"""""""". Therefore, gaining a thorough understanding of normal and pathological tau action is of fundamental importance. Mechanistically, tau serves at least many of its functions by regulating the growth and shortening dynamics of microtubules. Since proper regulation of microtubule dynamics is well-established to be essential for cell function and viability, neurons exert tight control over tau action. Indeed, tau activity is regulated by both alternative splicing of tau RNA and phosphorylation mechanisms. In the previous cycle of this project, we performed a detailed mechanistic analysis of the abilities of normal and FTDP-17 mutant tau isoforms to regulate microtubule dynamics, leading us to propose a mis-regulation of microtubule dynamics model in which properly regulated tau maintains MT dynamics within a defined range of tolerable activities whereas errors in tau action lead to inappropriate regulation of MT dynamics, which in turn leads to neuronal cell death and dementia. Here, we propose to superimpose phosphorylation mediated effects upon tau's ability to regulate microtubule dynamics in order to test the hypothesis that biologically relevant but inappropriate phosphorylation of tau compromises its ability to properly regulate microtubule dynamics, thereby promoting cell death. We will also test the hypothesis that inappropriate phosphorylation of tau exacerbates the FTDP- 17 mutation induced inability of tau to properly regulate microtubule dynamics, again promoting neuronal cell death. We will focus our efforts upon CDK/p25, GSKSp and MARK, three kinases with well-established in vivo relevance for tau as well as Pin1, a prolyl isomerase involved in regulating tau phosphorylation and strongly implicated in neurodegeneration. Briefly summarized, this proposal seeks to better understand the precise details underlying neuronal cell death leading to dementia. Achieving this goal will provide excellent potential targets for the development of rationally designed anti-dementia therapeutics.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Santa Barbara
Organized Research Units
Santa Barbara
United States
Zip Code
Chung, Peter J; Song, Chaeyeon; Deek, Joanna et al. (2016) Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment. Nat Commun 7:12278
Feinstein, H Eric; Benbow, Sarah J; LaPointe, Nichole E et al. (2016) Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action. J Neurochem 137:939-54
Chung, Peter J; Choi, Myung Chul; Miller, Herbert P et al. (2015) Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules. Proc Natl Acad Sci U S A 112:E6416-25
Yu, Dezhi; LaPointe, Nichole E; Guzman, Elmer et al. (2014) Tau proteins harboring neurodegeneration-linked mutations impair kinesin translocation in vitro. J Alzheimers Dis 39:301-14
Needleman, Daniel J; Ojeda-Lopez, Miguel A; Raviv, Uri et al. (2013) Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules. Faraday Discuss 166:31-45
Larini, Luca; Gessel, Megan Murray; LaPointe, Nichole E et al. (2013) Initiation of assembly of tau(273-284) and its ýýK280 mutant: an experimental and computational study. Phys Chem Chem Phys 15:8916-28
Iyer, Abhinaya; Lapointe, Nichole E; Zielke, Krzysztof et al. (2013) A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function. PLoS One 8:e76409
Reifert, Jack; Hartung-Cranston, DeeAnn; Feinstein, Stuart C (2011) Amyloid beta-mediated cell death of cultured hippocampal neurons reveals extensive Tau fragmentation without increased full-length tau phosphorylation. J Biol Chem 286:20797-811
Peck, Austin; Sargin, M Emre; LaPointe, Nichole E et al. (2011) Tau isoform-specific modulation of kinesin-driven microtubule gliding rates and trajectories as determined with tau-stabilized microtubules. Cytoskeleton (Hoboken) 68:44-55
Safinya, Cyrus R; Raviv, Uri; Needleman, Daniel J et al. (2011) Nanoscale assembly in biological systems: from neuronal cytoskeletal proteins to curvature stabilizing lipids. Adv Mater 23:2260-70

Showing the most recent 10 out of 29 publications