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Fig. 7 | Acta Neuropathologica Communications

Fig. 7

From: Nicotine promotes neuron survival and partially protects from Parkinson’s disease by suppressing SIRT6

Fig. 7

Nicotine does not rescue MPTP-induced DA neuron death in SIRT6 brain-specific knockout mice. a Quantification of histochemical analysis presented on (b). Boxplots display the relative density of DA neurons in the substantia nigra pars compacta assessed by stereological counting. Three-way ANOVA analysis: pgenotype = 0.57, pMPTP < 0.0001, pnicotine = 1.0. (b) Representative immuno-histochemical analysis of substantia nigra pars compacta of WT and BSKO mice treated with MPTP and or nicotine. Stained with TH to visualize DA neurons. (c) Bar graph of MAOB enzymatic activity from cortex homogenates. Total MAO activity was not different; residual MAOB activity was not different when MAOA was inhibited with clorgiline; nor residual MAOA activity was different when MAOB was inhibited with deprenyl. Mean ± SEM, N ≥ 3, pgenotype = 0.39, pinhibitors = 3.61•10− 14, pgenotype x inhibitors = 0.34 by two-way ANOVA). Together these data suggest that SIRT6 does not alter the metabolism of the neurotoxin MPTP. d Relative DAT1/VMAT2 ratio calculated from individual expression data from WT, BSKO, and BSOX brains. See also Additional file 1: Figure S3. One-way ANOVA p value shown. e A schematic of the mechanistic link between nicotine, SIRT6, and PD is illustrated. Our data demonstrates that SIRT6 plays a pathogenic role in initiation and progression of PD by stimulating TNFα release and suppressing AKT signaling, all of which promote neuronal apoptosis. SNPs associated with an increased risk of PD, such as rs107251 significantly increase SIRT6 abundance and therefore increase likelihood of neuronal apoptosis. Nicotine promotes proteasome-dependent degradation of SIRT6, which in turn protects cells from stress-induced apoptosis and prevents or ameliorates neurodegenerative pathologies. Selective targeting of SIRT6 might have a therapeutic effect against PD

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