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 neurondifferentiated, 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.

Back to the tubule: microtubule dynamics in Parkinson’s disease

“…Sirtuin 2 (SIRT2), an additional tubulin deacetylase has been shown to interact with soluble heterodimers as well as assembled microtubules [92]. Interestingly, the oxidative neurotoxin 6-hydroxydopamine (6OHDA) was shown to influence SIRT2 activity and microtubule dynamics through more than one mechanism, leading to impaired nuclear import of certain transcription factors [93, 94]. Consistently, altered subcellular localisation of transcription factors has been reported in post-mortem PD brains [93, 95, 96].…”

“…In all cases, deacetylase inhibitor therapy resulted in symptomatic alleviation. However, it should be noted that oxidative stress induced by the neurotoxin 6OHDA also reduces deacetylase activity via inhibition of SIRT2 [94]. This finding indicates that therapeutic effects of deacetylase inhibition may be context-dependent.…”

SIRT2 mediates NADH‐induced increases in Nrf2, GCL, and glutathione by modulating Akt phosphorylation in PC12 cells

“…Several experimental studies have suggested that SIRT2 reduction can produce beneficial effects on Parkinson's disease (PD) . Because cumulative evidence has indicated critical roles of oxidative stress in the pathogenesis of PD and other neurological diseases , it is of importance to investigate the potential relationship between SIRT2 and oxidative stress.…”

Nicotinamide Riboside Delivery Generates Nad+ Reserves to Protect Vascular Cells Against Oxidative Damage

“…SIRT2 has been reported to deacetylate α-tubulin, in an NAD + dependent manner (262,263). Changes in SIRT2 activity have been linked to altered microtubule dynamics (264). Further, agents that alter tubulin-mediated intracellular transport of DNA repair proteins worsen DNA damage repair (265).…”