Autophagy induced by the class III histone deacetylase Sirt1 prevents prion peptide neurotoxicity

Sirtuin 1 (Sirt1) is a class III histone deacetylase that mediates the protective effects of neurons in neurodegenerative disorders, including Alzheimer's and prion disease. However, the mechanism directly involved in neuroprotection is still poorly understood. Recent evidence has demonstrated that activating Sirt1 induces autophagy, and that activating autophagy protects neurons against neurodegenerative disorders by regulating mitochondrial homeostasis. Thus, we focused on the mechanism of the Sirt1-mediated neuroprotective effect that was associated with regulating mitochondrial homeostasis via autophagy. Adenoviral-mediated Sirt1 overexpression prevented prion protein (PrP)(106-126)-induced neurotoxicity via autophagy processing. Moreover, Sirt1-induced autophagy protected against the PrP(106-126)-mediated decrease in the mitochondrial membrane potential value. Additionally, Sirt1 overexpression decreased PrP(106-126)-induced Bax translocation to the mitochondria and cytochrome c release into the cytosol. Sirt1 knockdown using small interfering (si) RNAs induced downregulation of Sirt1 protein expression and sensitized neuron cells to PrP(106-126)-induced cell death and mitochondrial dysfunction. Knockdown of autophagy-related 5 (ATG5) using small interfering RNA decreased autophagy-related 5 and autophagy marker microtubule-associated protein 1 light chain 3-II protein levels and blocked the effect of a Sirt1 activator against PrP(106-126)-induced mitochondrial dysfunction and neurotoxicity. Taken together, this study is the first report demonstrating that autophagy induced by Sirt1 activation plays a pivotal role protecting against prion-induced neuron cell death and also suggests that regulating autophagy including which by Sirt1 activation may be a therapeutic target for neurodegenerative disorders including the prion disease.