HDAC6 alleviates prion peptide-mediated neuronal death via modulating PI3K-Akt-mTOR pathway.
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.
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Ting
T
Zhu
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Deming
D
Zhao
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Zhiqi
Z
Song
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Zhen
Z
Yuan
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Chaosi
C
Li
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Yunsheng
Y
Wang
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Xiangmei
X
Zhou
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Xiaomin
X
Yin
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Muhammad Farooque
MF
Hassan
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China. Electronic address: yanglf@cau.edu.cn.
Lifeng
L
Yang
D000818:Animals; D001343:Autophagy / Q000235:genetics; D016923:Cell Death / Q000235:genetics*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D019636:Neurodegenerative Diseases / Q000235:genetics; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011328:Prions / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D011328:Prions; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C082632:prion protein (106-126); C546842:MTOR protein, human; C499033:Hdac6 protein, mouse
Autophagy; HDAC6; Neuronal death; PI3K-Akt-mTOR; PrP106-126