期刊
EXPERIMENTAL NEUROLOGY
卷 257, 期 -, 页码 170-181出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2014.04.024
关键词
Microtubule dynamics; Oxidative stress; Parkinson's disease; Sirtuin
资金
- National Institutes of Health [R01 AG026389, R01 NS065789, T32-NS007433, F31-NS076040]
The microtubule (MT) system is important for many aspects of neuronal function, including motility, differentiation, and cargo trafficking. Parkinson's disease (PD) is associated with increased oxidative stress and alterations in the integrity of the axodendritic tree. To study dynamic mechanisms underlying the neurite shortening phenotype observed in many PD models, we employed the well-characterized oxidative parkinsonian neurotoxin, 6-hydroxydopamine (60HDA). In both acute and chronic sub-lethal settings, 60HDA-induced oxidative stress elicited significant alterations in MT dynamics, including reductions in MT growth rate, increased frequency of MT pauses/retractions, and increased levels of tubulin acetylation. Interestingly, 60HDA decreased the activity of tubulin deacetylases, specifically sirtuin 2 (SIRT2), through more than one mechanism. Restoration of tubulin deacetylase function rescued the changes in MT dynamics and prevented neurite shortening in neuron differentiated, 60HDA-treated cells. These data indicate that impaired tubulin deacetylation contributes to altered MT dynamics in oxidatively-stressed cells, conferring key insights for potential therapeutic strategies to correct MT-related deficits contributing to neuronal aging and disease. (C) 2014 Elsevier Inc. All rights reserved.
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