Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity

Neuron. 2008 Dec 10;60(5):803-17. doi: 10.1016/j.neuron.2008.10.015.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Cycle / physiology
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Chromatin Immunoprecipitation / methods
  • Comet Assay
  • Conditioning, Psychological / physiology
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / physiology*
  • DNA Breaks, Double-Stranded
  • DNA Damage / genetics
  • Fear / physiology
  • Gene Expression / genetics
  • Gene Expression Profiling / methods
  • Green Fluorescent Proteins / biosynthesis
  • Green Fluorescent Proteins / genetics
  • Histone Deacetylase 1
  • Histone Deacetylases / metabolism*
  • Humans
  • Ischemia / pathology
  • Ki-67 Antigen / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Degeneration / enzymology*
  • Nerve Degeneration / genetics
  • Nerve Tissue / metabolism
  • Neurons / physiology
  • Proliferating Cell Nuclear Antigen / metabolism
  • Prosencephalon / metabolism
  • Rats
  • Transfection

Substances

  • Ki-67 Antigen
  • Proliferating Cell Nuclear Antigen
  • Green Fluorescent Proteins
  • Cyclin-Dependent Kinase 5
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases