Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ATM-deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin as well as to MEF2A and CREB, leading to histone de-acetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts the neurodegenerative changes and rescues several behavioral abnormalities of Atm mutants. Full rescue, however, also requires HDAC4 in the cytoplasm, suggesting that the A-T phenotype results both from a loss of cytoplasmic HDAC4 and its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The HDAC4 phosphatase, PP2A, is down regulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and nuclear accumulation. Our results define a crucial role of nuclear accumulation and cytoplasmic depletion of HDAC4 in the events leading to A-T neurodegeneration.