Multi-scale analysis and modeling of acetylation effects on neuronal microtubules

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.