Neuronal function and plasticity require the capacity to stabilize certain microtubule populations, as well as the ability to make new microtubules. Microtubules are also essential for the maintenance of mature neuronal form and function. Abnormalities observed in aging brain (loss of dendritic spines, loss of plasticity) may result from abnormal modulation of microtubule stability. Thus understanding the regulation of neuronal form and function will depend at least partially in understanding the mechanisms that regulate microtubule assembly and stability. Microtubules comprised of tubulin that has been acetylated have been shown to be more stable. To determine whether tubulin acetylation regulates microtubule stability in neurons, we will acetylate brain microtubules in vitro, and determine whether their cold-stability is altered either directly, or indirectly due to effects on the binding of microtubule-associated proteins. Microtubules or structures containg acetylated tubulin will be analyzed morphologically, immunochemically and biochemically in cold-stable fractions already identified in bovine brain homogenate as enriched for acetylated tubulin. For a total profile, we will quantify total and acetylated tubulin, and the enzymes that regulate the levels of the latter, during postnatal rat brain development, maturation, and senescence. Experiments such as these, that attempt to identify regulatory mechanisms in neuronal microtubule assembly, are essential for understanding the regulation of normal neuronal form and function, and how these may be altered in aged and diseased brain.
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