ABSTRACT
Histone deacetylase 6 (HDAC6) controls several major cellular responses to stress that play a role in neurodegenerative diseases, including aggresome formation, autophagy, and apoptosis. However, the specific role of HDAC6 in prion diseases is not known. In this study, we examined the relationship between HDAC6 and cellular response to the neurotoxic synthetic prion protein fragment PrP106-126. We determined that exposure of cerebral cortical neurons to this fragment alters the expression and localization of HDAC6. Suppression of HDAC6 activity or knockdown of HDAC6 expression exacerbates the neuronal cell death induced by PrP106-126, but that overexpression of HDAC6 alleviates PrP106-126-induced neuronal death. We also found that this protective effect of HDAC6 involves the activation of autophagy and modulation of PI3K-Akt-mammalian target of rapamycin (mTOR) signaling. Overexpression of HDAC6 in neurons-induced autophagy correlated with a reduction in phosphorylated mTOR and phosphorylated p70S6K in response to PrP106-126 stimulation, conversely, HDAC6 deficiency interfered with autophagy and increased phosphorylated mTOR and phosphorylated 70S6K. In addition, HDAC6 also appears to modulate the phosphorylation of Akt; overexpression of HDAC6 increased the phosphorylated Akt, but HDAC6 deficiency resulted in further reduction of phosphorylated Akt. Overall, we demonstrate that HDAC6 protects neurons from toxicity of prion peptide, and that this protection occurs at through the regulation of the PI3k-Akt-mTOR axis.
