Mechanism & Control of Brain Microtubule Dynamics

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DESCRIPTION (provided by applicant): Microtubules (MTs), tube-shaped polymers composed of ab 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 dendntic processes of neurons. MTs are not simple equilibrium polymers. Guanosine-5'-triphosphate is irreversibly hydrolyzed to guanosine-5'-diphosphate and orthophosphate during tubulin addition to the MTs, which creates two unique dynamic behaviors, treadmilling and dynamic instability. These behaviors are critical for MT function in cells, and are finely regulated. Both dynamic instability and treadmilling are intrinsic properties of the tubulin backbone of MTs, while MAPs acting at the MT surfaces and ends control the dynamics. One major goal is to elucidate the mechanisms responsible for the MT's unique dynamic behaviors. A second major goal is to determine how important neuronal MAPs regulate dynamics. These studies will involve high-resolution video microscopy and radiolabeled guanine-nucleotide exchange strategies. Studies will focus on the dynamics of reconstituted brain MTs and specific neuronal MAPs in vitro, and on MT dynamics in living neuronal and non-neuronal cells. A main focus will be on the tau proteins and mutated forms of tau, which are involved in Alzheimer's disease and are causally linked to frontotemporal dementias (FTDP-17) in humans.