Mechanism and Control of Brain Microtubule Dynamics

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DESCRIPTION (provided by applicant): Microtubules are dynamic polymers that are critical in the determination and maintenance of cell shape, polarity, and in many types of cellular movement. They exhibit two unique dynamic behaviors, dynamic instability and treadmilling, which are important determinants of their functions in cells. Both dynamic behaviors are intrinsic properties of the tubulin backbone, while microtubule-associated proteins acting at the surface or ends of microtubules control the dynamics. The expression of microtubule- associated proteins that regulate microtubule behavior is significantly altered during neuronal development, and their mis-regulation contributes to human diseases including cancer and neurodegeneration. This proposal is based upon a considerable body of knowledge indicating that 1) microtubules have a large number of binding sites along their surfaces and at their ends that serve as the targets for cellular regulatory molecules and 2) that the binding of small numbers of such regulatory molecules to their specific sites exerts powerful effects on the dynamic behaviors and, thus, the functions of the microtubules. By using a combination of in vitro mechanistic approaches together with analysis in cells, the focus will be on the mechanisms that determine and control the dynamic instability and treadmilling behaviors of microtubules. It will involve determination how the tau proteins, which stabilize microtubules and may mis-regulate dynamics in neurodegenerative tauopathies such as Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and the stathmin/SCG10 family of microtubule destabilizing proteins, act mechanistically to modulate dynamics. The goals are 1) to elucidate at a mechanistic/biochemical level in vitro, and behaviorally in living cells, how the tau proteins regulate dynamic instability and treadmilling, how FTDP-17 mutated forms of tau mis-regulate the dynamics, and how microtubule-targeted drugs can correct the mis-regulation, 2) to determine at a mechanistic/biochemical level in vitro, and behaviorally in living cells, how the stathmin and SCG10 family of microtubule destabilizing proteins regulates dynamic instability, treadmilling, and minus end dynamics, and 3) to determine the size and chemical nature of the stabilizing cap at microtubule ends, and to use microtubule-associated proteins that modulate dynamics as tools to determine how the cap mechanism is regulated.