title: Decreased SIRT2 activity leads to altered microtubule dynamics in oxidatively-stressed neuronal cells: implications for Parkinson's disease.
abstract: 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 (6OHDA). In both acute and chronic sub-lethal settings, 6OHDA-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, 6OHDA 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, 6OHDA-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.
authors.affiliation: Department of Pathology, Division of Neuropathology, 3550 Terrace St., University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: vpp3@pitt.edu.
authors.forename: Vivek P
authors.initials: VP
authors.lastname: Patel
authors.affiliation: Department of Pathology, Division of Neuropathology, 3550 Terrace St., University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA; The McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15213, USA; The Pittsburgh Institute for Neurodegenerative Diseases, Pittsburgh, PA 15213, USA. Electronic address: ctc4@pitt.edu.
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003172:Complement C1 / Q000235:genetics; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D003172:Complement C1; D008164:Luminescent Proteins; C403664:MAPRE3 protein, human; D008869:Microtubule-Associated Proteins; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D014212:Tretinoin; D016627:Oxidopamine; D007770:L-Lactate Dehydrogenase; C474199:SIRT2 protein, human; D056565:Sirtuin 2; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Microtubule dynamics; Oxidative stress; Parkinson's disease; Sirtuin