title: Increased acetylation of Peroxiredoxin1 by HDAC6 inhibition leads to recovery of Aβ-induced impaired axonal transport.
abstract: Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer's disease (AD) and is recently being considered a possible therapeutic strategy. However, the restoring mechanism of HDAC6 inhibition has not been fully understood.
  
  
  
  Here, we found that an anti-oxidant protein Peroxdiredoxin1 (Prx1), a substrate of HDAC6, malfunctions in Aβ treated cells, the brains of 5xFAD AD model mice and AD patients. Malfunctioning Prx1, caused by reduced Prx1 acetylation levels, was recovered by HDAC6 inhibition. Increasing acetylation levels of Prx1 by HDAC6 inhibition recovered elevated reactive oxygen species (ROS) levels, elevated Ca2+levels and impaired mitochondrial axonal transport, sequentially, even in the presence of Aβ. Prx1 mutant studies on the K197 site for an acetylation mimic or silencing mutation support the results showing that HDAC6 inhibitor restores Aβ-induced disruption of ROS, Ca2+and axonal transport.
  
  
  
  Taken together, increasing acetylation of Prx1 by HDAC6 inhibition has several beneficial effects in AD pathology. Here, we present the novel mechanism by which elevated acetylation of Prx1 rescues mitochondrial axonal transport impaired by Aβ. Therefore, our results suggest that modulation of Prx1 acetylation by HDAC6 inhibition has great therapeutic potential for AD and has further therapeutic possibilities for other neurodegenerative diseases as well.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Heesun
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Haeng Jun
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Jisoo
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University, College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Soohyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Wonik
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Laboratory of Immunology and Cancer Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yeonju
authors.initials: Y
authors.lastname: Park
authors.affiliation: Center for Neuromedicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea.
authors.forename: Seung Jae
authors.initials: SJ
authors.lastname: Hyeon
authors.affiliation: Department of Biomedical Sciences, Laboratory of Immunology and Cancer Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
authors.affiliation: VA Boston Healthcare System, Boston University Alzheimer's Disease Center, and Department of Neurology, Boston University School of Medicine, Boston, MA02130, USA.|Center for Neuromedicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University, College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Junho
authors.initials: J
authors.lastname: Chung
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea. inhee@snu.ac.kr.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D056572:Histone Deacetylase Inhibitors; D054464:Peroxiredoxins; D006655:Histone Deacetylases
keywords: Alzheimer’s disease; Axonal transport; Histone deacetylase 6; Oxidative stress; Peroxiredoxin1; Reactive oxygen species