HDAC6 Alleviates Neurotoxic Prion Peptide-induced Neuronal Death And Its Mechanism

Transmissible Spogiform Encephalopathies (TSEs), also known as Prion diseases, which are progressive fatal neurodegenerative diseases and pathologically characterized by brain vacuolation, neuronal cell death and astrocytosis. They are caused by the conversion of cellular prion protein (PrPc) into pathological isoform (PrPSc) through conformational changes. The Autophagy-lysosome pathway is known as an important degradation system of misfolded proteins and impaired mitochondrias to defend neurodegeneration. Additionally, many studies found that enhance autophagy can induce clearance of protease resistant prion protein and protect neuronal cells from death in vivo and vitro. Additionally, an increasing number of studies suggest that a histone deacetylase 6 (HDAC6) plays important roles in neurodegenrative diseases; HDAC6 also have a structure of ZnF-UBP beside the deacetylase activity, which is different from other histone deacetylases, so it can bind ubiquitinated misfolded protein. Beacause of these structures, HDAC6 have multiple functions, and recently it has already becoming the target for the pathogenesis and therapy of neurodegenrative diseases. We study in exploring the function of HDAC6 in prion diseases, and then provide new ideas for the pathogenesis and therapy of prion diseases. Our study first assessed the expression and location of HDAC6 in neurons treated with PrP 106-126 and investigated the relationship between HDAC6 and the toxicity of PrP 106-126. And then, we investigated the influence of HDAC6 on autophagy and PI3K-Akt-mTOR axis.The results found that:(1) PrP 106-126 changed the expression of HDAC6 and caused a dramatic relocation of HDAC6 to a single prominent corpuscle in the perinuclear region. Additionally, HDAC6 participate in regulation the toxicity of PrP106-126, suppression of HDAC6 activity by Tubacin or knockdown of HDAC6 using short hairpin RNA exacerbates the neuronal cell death induced by PrP 106-126, and that overexpression of HDAC6 alleviates PrP106-126-induced neuronal cell death, which indicate that HDAC6 participates to resist the toxicity of PrP106-126 in the neurons.(2) Subsequente study showed that autophagic inhibitors:3-MA and Bafilomycin Al could abort the protection of HDAC6 in response to PrP106-126-induced neuronal death, which mean that autophagy is involved in the protection of HDAC6 against PrP106-126-induced neuronal death. Further study showed that overexpression of HDAC6 increased autophgic flux in response to PrP 106-126, while, inhibition the activity of HDAC6 or knockdown of HDAC6 protein reduced autophagy.(3) Further study suggested that overexpression of HDAC6 in primary neurons reduced phosphorylated mTORCl and phosphorylated 70S6K in response to PrP106-126 stimulation, while knockdown of HDAC6 using short hairpin RNA resulted in increased phosphorylated mTORCl and phosphorylated 70S6K. Furthermore, HDAC6 also appears to modulate the phosphorylation of Akt, a prosurvival factor, we found that PrP106-126 reduced the phosphorylated Akt in primary neurons and overexpression of HDAC6 in primary neurons could restore the phosphorylated Akt, in the contrary, knockdown of HDAC6 resulted in a further reduction of phosphorylation of Akt in response to PrP106-126. Cell viability assays demonstrated that wortmanin, an inhibitor of PI3K-Akt, also inhibited the protection of HDAC6, while, IGF-1 which can activate PI3K-Akt could prevent HDAC6-knockdown neurons from PrP106-126-induced neuronal death. Overall, we demonstrate that HDAC6 protects neurons from prion peptide-induced neuronal death, and that this protection occurs at through the regulation of the PI3k-Akt-mTOR axis.