title: p53-dependent SIRT6 expression protects Aβ42-induced DNA damage.
abstract: Alzheimer's disease (AD) is the most common type of dementia and age-related neurodegenerative disease. Elucidating the cellular changes that occur during ageing is an important step towards understanding the pathogenesis and progression of neurodegenerative disorders. SIRT6 is a member of the mammalian sirtuin family of anti-aging genes. However, the relationship between SIRT6 and AD has not yet been elucidated. Here, we report that SIRT6 protein expression levels are reduced in the brains of both the 5XFAD AD mouse model and AD patients. Aβ42, a major component of senile plaques, decreases SIRT6 expression, and Aβ42-induced DNA damage is prevented by the overexpression of SIRT6 in HT22 mouse hippocampal neurons. Also, there is a strong negative correlation between Aβ42-induced DNA damage and p53 levels, a protein involved in DNA repair and apoptosis. In addition, upregulation of p53 protein by Nutlin-3 prevents SIRT6 reduction and DNA damage induced by Aβ42. Taken together, this study reveals that p53-dependent SIRT6 expression protects cells from Aβ42-induced DNA damage, making SIRT6 a promising new therapeutic target for the treatment of AD.
authors.affiliation: Department of Biochemistry &Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Jung
authors.affiliation: Department of Biochemistry &Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry &Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Hyundong
authors.initials: H
authors.lastname: Song
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry &Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Ahbin
authors.initials: A
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Korea.|Department of Neurology and Pathology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Department of Biochemistry &Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
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 / Q000633:toxicity*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D037761:Sirtuins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000873:Anthracenes; D006657:Histones; D007093:Imidazoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C432165:pyrazolanthrone; C482205:nutlin 3; C501860:Sirt6 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; C516592:SIRT6 protein, human; D037761:Sirtuins; D008239:Lysine