Neuroprotection by histone deacetylase-related protein

Brad E. Morrison, Nazanin Majdzadeh, Xiaoguang Zhang, Aaron Lyles, Rhonda Bassel-Duby, Eric N. Olson, Santosh R. D'Mello

Research output: Contribution to journalArticle

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Abstract

The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons cultured from mice lacking HDRP are more vulnerable to cell death. Adenovirally mediated expression of HDRP prevents neuronal death, showing that HDRP is a neuroprotective protein. Neuroprotection by forced expression of HDRP is not accompanied by activation of the phosphatidylinositol 3-kinase-Akt or Raf-MEK-ERK signaling pathway, and treatment with pharmacological inhibitors of these pathways fails to inhibit the neuroprotection by HDRP. Stimulation of c-Jun phosphorylation and expression, an essential feature of neuronal death, is prevented by HDRP. We found that HDRP associates with c-Jun N-terminal kinase (JNK) and inhibits its activity, thus explaining the inhibition of c-Jun pliosphorylation by HDRP. HDRP also interacts with histone deacetylase 1 (HDAC1) and recruits it to the c-Jun gene promoter, resulting in an inhibition of histone H3 acetylation at the c-Jun promoter. Although HDRP lacks intrinsic deacetylase activity, treatment with pharmacological inhibitors of histone deacetylases induces apoptosis even in the presence of ectopically expressed HDRP, underscoring the importance of c-Jun promoter deacetylation by HDRP-HDAC1 in HDRP-mediated neuroprotection. Our results suggest that neuroprotection by HDRP is mediated by the inhibition of c-Jun through its interaction with JNK and HDAC1.

Original languageEnglish (US)
Pages (from-to)3550-3564
Number of pages15
JournalMolecular and Cellular Biology
Volume26
Issue number9
DOIs
StatePublished - May 2006

Fingerprint

Histone Deacetylases
Proteins
Histone Deacetylase 1
Neuroprotection
Neurons
Cell Death
jun Genes
Phosphatidylinositol 3-Kinase
Pharmacology
Apoptosis
MAP Kinase Signaling System
JNK Mitogen-Activated Protein Kinases
Antisense Oligonucleotides
Acetylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Neuroprotection by histone deacetylase-related protein. / Morrison, Brad E.; Majdzadeh, Nazanin; Zhang, Xiaoguang; Lyles, Aaron; Bassel-Duby, Rhonda; Olson, Eric N.; D'Mello, Santosh R.

In: Molecular and Cellular Biology, Vol. 26, No. 9, 05.2006, p. 3550-3564.

Research output: Contribution to journalArticle

Morrison, Brad E. ; Majdzadeh, Nazanin ; Zhang, Xiaoguang ; Lyles, Aaron ; Bassel-Duby, Rhonda ; Olson, Eric N. ; D'Mello, Santosh R. / Neuroprotection by histone deacetylase-related protein. In: Molecular and Cellular Biology. 2006 ; Vol. 26, No. 9. pp. 3550-3564.
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