MECHANISM AND CONTROL OF BRAIN MICROTUBULE DYNAMICS

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DESCRIPTION: Microtubules (MTs), tube-shaped polymers composed of a-b tubulin heterodimers and a diverse array of MT-associated proteins (MAPs), are critical for the development, structural organization, stability, and functions of the axonal and dendritic processes of neurons. However, MT functions in neurons and other cells at the molecular level are poorly understood. Microtubules polymerize by a nucleation-elongation mechanism but they are not simple equilibrium polymers. Guanosine-5'-triphosphate is hydrolyzed to guanosine-5'-diphosphate and orthophosphate during tubulin addition to the MT ends, which is hypothesized to create a stabilizing "cap" at the ends. Gain and loss of the cap create unique growing and shortening dynamics that are critical for microtubule function. The dynamics are finely regulated in cells. Regulation of MT dynamics is effected by a variety of MAPs, by the tubulin isotype composition of a MT, and by factors acting on the "cap" mechanism. This study is focused on the mechanism and regulation of MT dynamics in vitro . The goals are to elucidate the mechanisms that determine and control MT dynamics. A major aim is to determine how the neuronal MAPs, tau, MAP1B, MAP2, and MAPIA, control steady-state dynamics. These studies will involve use of high resolution video microscopy and radiolabeled guanine-nucleotide exchange strategies to investigate dynamics in relation to MAP binding to the MTs, to the Mts, to the action of the MAPs on steady-state rates of GTP hydrolysis, and to the actions of the MAPs on the size and chemical nature of the stabilizing cap. A hyper-phosphorylated form of tau is the main protein component of the paired helical filaments in the neurofibrillary tangles of patients with Alzheimer's disease. Thus, understanding how tau controls MT stability may eventually lead to the development of tau-like drugs for the treatment of Alzheimer's disease. The second aim is to determine how the b- tubulin isotype composition regulated steady-state MT dynamics and function. The third aim is to elucidate how the drug colchicine modulates MT dynamics. Understanding the mechanism of action of colchicine may reveal how regulatory factors in cells acting at MT ends might modulate MT dynamics and function. The fourth aim is to elucidate the capping mechanism responsible for the MT's unique dynamic behaviors.