MICROTUBULE DYNAMICS IN OXIDATIVELY-STRESSED NEURONAL CELLS

The microtubule (MT) system is important for many aspects of neuronal function, including motility, differentiation, and organelle trafficking. The dysregulation of this system can therefore have a significant impact on neuronal function and survival. Parkinson’s disease (PD) is associated with alterations in integrity of the axon/dendrites as well as axonal transport, which is suggestive of altered MT function. In fact, recent studies using genetic and toxin models are beginning to implicate MT dysfunction as a key mechanism underlying neuronal degeneration in PD. To further study the role of MT dysfunction in PD neurodegeneration, the effects of oxidative stress, which plays a key role in PD pathogenesis, on MT function were examined using the commonly utilized PD toxin, 6-hydroxydopamine (6OHDA). In response to 6OHDA-induced oxidative stress in neuronal cells, significant alterations in MT function were observed with reductions in MT growth rate, increase in frequency of MT pauses/retractions, impaired end binding protein 1 (EB1) levels, and increase in levels of tubulin acetylation. Impaired function of tubulin deacetylases, specifically sirtuin 2 (SIRT2), was observed in oxidatively-stressed cells. Restoration of tubulin deacetylase function rescued MT function and the neuritic degeneration phenotype observed in response to 6OHDA, suggesting that oxidative stress impairs MT function by altering tubulin acetylation. In addition to its impact on the integrity of the neurite, oxidative disruption of MT function also affected MT-dependent nuclear transport, which could contribute to the selective declines in transcriptional responses of diseased dopaminergic neurons. In all, this study provides support for the role of MT dysfunction in the degenerative processes seen in PD. Elucidating how oxidative stress-induced changes in MT function can lead to neuronal degeneration will provide key insight into the development of novel therapeutic strategies