title: Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity.
abstract: Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death.
authors.affiliation: Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Dohoon
authors.initials: D
authors.lastname: Kim
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Frank
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Dobbin
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Tsunemoto
authors.forename: Weihong
authors.initials: W
authors.lastname: Tu
authors.forename: Peter L
authors.initials: PL
authors.lastname: Peng
authors.forename: Ji-Song
authors.initials: JS
authors.lastname: Guan
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.forename: Paola
authors.initials: P
authors.lastname: Giusti
authors.forename: Nisha
authors.initials: N
authors.lastname: Broodie
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Ivanna
authors.initials: I
authors.lastname: Delalle
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Youming
authors.initials: Y
authors.lastname: Lu
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D000090266:Chromobox Protein Homolog 5; D020552:Comet Assay; D003213:Conditioning, Psychological / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D005239:Fear / Q000502:physiology; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics; D009417:Nerve Tissue / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D051381:Rats; D014162:Transfection
chemical_list: C000715594:CBX5 protein, human; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D000090266:Chromobox Protein Homolog 5; D049452:Green Fluorescent Proteins; D051360:Cyclin-Dependent Kinase 5; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases