Chromatin localization of HDAC4 in ATM-/- mice

Ataxia-telangiectasia (A-T) is caused by mutation of the ATM (A-T mutated) gene. ATM functions in the DNA damage response, but how its loss causes neuronal loss is unclear. We report here that HDAC4 plays a role in the process of neurodegeneration. Histone deacetylases are nuclear proteins, but when it is phosphorylated HDAC4 is cytoplasmic. As the activity of the HDAC4 phosphatase, PP2A, is down regulated by the ATM kinase, ATM deficiency enhances PP2A activity. This leads to HDAC4 dephosphorylation, accumulation in the nucleus and global histone de-acetylation. Nuclear HDAC4 directly suppresses MEF2A- and CREB-dependent transcriptional activities as well as other multiple neuronal gene expression including BDNF and this effect is mediated by its binding directly to the regulatory regions of these genes. Our findings suggest that nuclear accumulation of HDAC4 is a key factor in the degeneration of neurons in A-T.