Microtubules are essential to virtually all aspects of neuronal activity, and post-translational modifications are thought to be key regulators of microtubule function. Microtubule acetylation is a post-translational modification that plays an important role in basic cellular activities, such as intracellular trafficking, that underlie normal neuronal function. However, fundamental questions remain: first, how do stable, but not dynamic, neuronal microtubules accumulate acetylation? Second, how does microtubule acetylation affect neuronal microtubule networks and neuronal structure? In this work, we will use biophysical and cellular experiments to elucidate whether the ?-tubulin lysine 40 acetyltransferase ?TAT1 preferentially acetylates stable microtubules, or whether ?TAT1 does not preferentially acetylate stable microtubules, but rather acts to select against dynamic microtubules. Then, we will develop a multi-scale, mechanistic computational model to integrate, interpret, and extend our experimental results. We will then leverage this framework to investigate previously uncharacterized ?-tubulin acetylation sites. These experiments and computer simulations will provide insights into how a post-translational modification that is enriched on neuronal microtubules affects neuronal morphogenesis, which has broad implications for a range of human disorders that are linked to dysfunction of the microtubule cytoskeleton, including Huntington's and Parkinson's diseases.
Neuronal communication relies on microtubules, which function as both structural elements and ?railroad tracks? that mediate transportation inside of neurons. Acetylation is a post-translational modification of microtubules that is thought to play an important role in fundamental cellular processes ranging from trafficking to endocytosis to the organization of organelles. In this study, we will use biophysical and cellular experiments, along with computational modeling, to elucidate the role of acetylation in determining the organization and remodeling of the neuronal microtubule cytoskeleton, which has broad implications for a range of human disorders that are linked to dysfunction of the microtubule cytoskeleton.
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| Jenkins, Brian V; Saunders, Harriet A J; Record, Helena L et al. (2017) Effects of mutating ?-tubulin lysine 40 on sensory dendrite development. J Cell Sci 130:4120-4131 |
