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Molecular and Cellular Biology, May 2006, p. 3550-3564, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3550-3564.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Neuroprotection by Histone Deacetylase-Related Protein{dagger}

Brad E. Morrison,1 Nazanin Majdzadeh,1 Xiaoguang Zhang,1 Aaron Lyles,1 Rhonda Bassel-Duby,2 Eric N. Olson,2 and Santosh R. D'Mello1*

Department of Molecular and Cell Biology, University of Texas at Dallas, 2601 N. Floyd Rd., Richardson, Texas 75083,1 Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 753902

Received 27 July 2005/ Returned for modification 10 September 2005/ Accepted 7 February 2006

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 phosphorylation 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.

* Corresponding author. Mailing address: Department of Molecular and Cell Biology, University of Texas at Dallas, 2601 N. Floyd Road, Richardson, TX 75083. Phone: (972) 883-2520. Fax: (972) 883-2409. E-mail: dmello{at}utdallas.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2006, p. 3550-3564, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3550-3564.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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