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PMID:22848598

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Citation

Pirooznia, SK, Sarthi, J, Johnson, AA, Toth, MS, Chiu, K, Koduri, S and Elefant, F (2012) Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer's disease model. PLoS ONE 7:e41776

Abstract

Histone acetylation of chromatin promotes dynamic transcriptional responses in neurons that influence neuroplasticity critical for cognitive ability. It has been demonstrated that Tip60 histone acetyltransferase (HAT) activity is involved in the transcriptional regulation of genes enriched for neuronal function as well as the control of synaptic plasticity. Accordingly, Tip60 has been implicated in the neurodegenerative disorder Alzheimer's disease (AD) via transcriptional regulatory complex formation with the AD linked amyloid precursor protein (APP) intracellular domain (AICD). As such, inappropriate complex formation may contribute to AD-linked neurodegeneration by misregulation of target genes involved in neurogenesis; however, a direct and causative epigenetic based role for Tip60 HAT activity in this process during neuronal development in vivo remains unclear. Here, we demonstrate that nervous system specific loss of Tip60 HAT activity enhances APP mediated lethality and neuronal apoptotic cell death in the central nervous system (CNS) of a transgenic AD fly model while remarkably, overexpression of Tip60 diminishes these defects. Notably, all of these effects are dependent upon the C-terminus of APP that is required for transcriptional regulatory complex formation with Tip60. Importantly, we show that the expression of certain AD linked Tip60 gene targets critical for regulating apoptotic pathways are modified in the presence of APP. Our results are the first to demonstrate a functional interaction between Tip60 and APP in mediating nervous system development and apoptotic neuronal cell death in the CNS of an AD fly model in vivo, and support a novel neuroprotective role for Tip60 HAT activity in AD neurodegenerative pathology.

Links

PubMed PMC3406101 Online version:10.1371/journal.pone.0041776

Keywords

Alzheimer Disease/enzymology; Alzheimer Disease/metabolism; Alzheimer Disease/pathology; Amyloid beta-Protein Precursor/metabolism; Animals; Apoptosis; Brain/enzymology; Brain/growth & development; Brain/metabolism; Brain/pathology; Disease Models, Animal; Drosophila Proteins/metabolism; Drosophila melanogaster/enzymology; Drosophila melanogaster/metabolism; Female; Gene Expression Regulation; Histone Acetyltransferases/metabolism; Humans; Male; Neurons/enzymology; Neurons/metabolism; Neurons/pathology; Transcription, Genetic

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:TIP60

involved_in

GO:0043524: negative regulation of neuron apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:TIP60

involved_in

GO:0010468: regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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