RGD Reference Report - Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia. - Rat Genome Database

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

Authors: Li, J  Chen, J  Ricupero, CL  Hart, RP  Schwartz, MS  Kusnecov, A  Herrup, K 
Citation: Li J, etal., Nat Med. 2012 May;18(5):783-90. doi: 10.1038/nm.2709.
RGD ID: 9681455
Pubmed: PMID:22466704   (View Abstract at PubMed)
PMCID: PMC3378917   (View Article at PubMed Central)
DOI: DOI:10.1038/nm.2709   (Journal Full-text)

Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ataxia telangiectasia treatmentIDA 9681455 RGD 
ataxia telangiectasia  IEP 9681455; 9681455protein:altered localization:nucleus:RGD 
ataxia telangiectasia  ISOHdac4 (Mus musculus)9681455; 9681455protein:altered localization:nucleus:RGD 
ataxia telangiectasia treatmentISOHDAC4 (Homo sapiens)9681455; 9681455 RGD 
ataxia telangiectasia  ISOHDAC4 (Homo sapiens)9681455; 9681455protein:altered localization:nucleus:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hdac4  (histone deacetylase 4)

Genes (Mus musculus)
Hdac4  (histone deacetylase 4)

Genes (Homo sapiens)
HDAC4  (histone deacetylase 4)


Additional Information