Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death

Timothy A Bolger, Tso Pang Yao

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Histone deacetylase 4 (HDAC4) undergoes signal-dependent shuttling between the cytoplasm and nucleus, which is regulated in part by calcium/calmodulin- dependent kinase (CaMK)-mediated phosphorylation. Here, we report that HDAC4 intracellular trafficking is important in regulating neuronal cell death. HDAC4 is normally localized to the cytoplasm in brain tissue and cultured cerebellar granule neurons (CGNs). However, in response to low-potassium or excitotoxic glutamate conditions that induce neuronal cell death, HDAC4 rapidly translocates into the nucleus of cultured CGNs. Treatment with the neuronal survival factor BDNF suppresses HDAC4 nuclear translocation, whereas a proapoptotic CaMK inhibitor stimulates HDAC4 nuclear accumulation. Moreover, ectopic expression of nuclear-localized HDAC4 promotes neuronal apoptosis and represses the transcriptional activities of myocyte enhancer factor 2 and cAMP response element-binding protein, survival factors in neurons. In contrast, inactivation of HDAC4 by small interfering RNA or HDAC inhibitors suppresses neuronal cell death. Finally, an increase of nuclear HDAC4 in granule neurons is also observed in weaver mice, which harbor a mutation that promotes CGN apoptosis. Our data identify HDAC4 and its intracellular trafficking as key effectors of multiple pathways that regulate neuronal cell death.

Original languageEnglish (US)
Pages (from-to)9544-9553
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number41
DOIs
StatePublished - Oct 12 2005
Externally publishedYes

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Histone Deacetylases
Cell Death
Neurons
Calcium-Calmodulin-Dependent Protein Kinases
Histone Deacetylase Inhibitors
Cytoplasm
MEF2 Transcription Factors
Neurologic Mutant Mice
Apoptosis
Cerebellar Nuclei
Cyclic AMP Response Element-Binding Protein
Brain-Derived Neurotrophic Factor
Small Interfering RNA
Glutamic Acid
Potassium
Phosphorylation
Calcium
Mutation
Brain

Keywords

  • Apoptosis
  • Cell death
  • Deacetylase
  • HDAC4
  • MEF2
  • Neuron

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death. / Bolger, Timothy A; Yao, Tso Pang.

In: Journal of Neuroscience, Vol. 25, No. 41, 12.10.2005, p. 9544-9553.

Research output: Contribution to journalArticle

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