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Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration.

ABSTRACT: Apoptosis is an essential cellular process in multiple diseases and a major pathway for neuronal death in neurodegeneration. The detailed signaling events/pathways leading to apoptosis, especially in neurons, require further elucidation. Here we identify a β-amyloid precursor protein (APP)-interacting protein, designated as appoptosin, whose levels are upregulated in brain samples from Alzheimer's disease and infarct patients, and in rodent stroke models, as well as in neurons treated with β-amyloid (Aβ) and glutamate. We further demonstrate that appoptosin induces reactive oxygen species release and intrinsic caspase-dependent apoptosis. The physiological function of appoptosin is to transport/exchange glycine/5-amino-levulinic acid across the mitochondrial membrane for heme synthesis. Downregulation of appoptosin prevents cell death and caspase activation caused by glutamate or Aβ insults. APP modulates appoptosin-mediated apoptosis through interaction with appoptosin. Our study identifies appoptosin as a crucial player in apoptosis and a novel pro-apoptotic protein involved in neuronal cell death, providing a possible new therapeutic target for neurodegenerative disorders.

SUBMITTER: Zhang H

PROVIDER: S-EPMC3509748 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration.

Zhang Han H Zhang Yun-wu YW Chen Yaomin Y Huang Xiumei X Zhou Fangfang F Wang Weiwei W Xian Bo B Zhang Xian X Masliah Eliezer E Chen Quan Q Han Jing-Dong J JD Bu Guojun G Reed John C JC Liao Francesca-Fang FF Chen Ye-Guang YG Xu Huaxi H

The Journal of neuroscience : the official journal of the Society for Neuroscience 20121001 44

Apoptosis is an essential cellular process in multiple diseases and a major pathway for neuronal death in neurodegeneration. The detailed signaling events/pathways leading to apoptosis, especially in neurons, require further elucidation. Here we identify a β-amyloid precursor protein (APP)-interacting protein, designated as appoptosin, whose levels are upregulated in brain samples from Alzheimer's disease and infarct patients, and in rodent stroke models, as well as in neurons treated with β-amy ...[more]

PMID: 23115192

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Project description:We previously demonstrated that protein kinase C? (PKC?; PKC delta) is an oxidative stress-sensitive kinase that plays a causal role in apoptotic cell death in neuronal cells. Although PKC? activation has been extensively studied, relatively little is known about the molecular mechanisms controlling PKC? expression. To characterize the regulation of PKC? expression, we cloned an ?2-kbp 5'-promoter segment of the mouse Prkcd gene. Deletion analysis indicated that the noncoding exon 1 region contained multiple Sp sites, including four GC boxes and one CACCC box, which directed the highest levels of transcription in neuronal cells. In addition, an upstream regulatory region containing adjacent repressive and anti-repressive elements with opposing regulatory activities was identified within the region -712 to -560. Detailed mutagenesis studies revealed that each Sp site made a positive contribution to PKC? promoter expression. Overexpression of Sp family proteins markedly stimulated PKC? promoter activity without any synergistic transactivating effect. Furthermore, experiments in Sp-deficient SL2 cells indicated long isoform Sp3 as the essential activator of PKC? transcription. Importantly, both PKC? promoter activity and endogenous PKC? expression in NIE115 cells and primary striatal cultures were inhibited by mithramycin A. The results from chromatin immunoprecipitation and gel shift assays further confirmed the functional binding of Sp proteins to the PKC? promoter. Additionally, we demonstrated that overexpression of p300 or CREB-binding protein increases the PKC? promoter activity. This stimulatory effect requires intact Sp-binding sites and is independent of p300 histone acetyltransferase activity. Finally, modulation of Sp transcriptional activity or protein level profoundly altered the cell death induced by oxidative insult, demonstrating the functional significance of Sp-dependent PKC? gene expression. Collectively, our findings may have implications for development of new translational strategies against oxidative damage.

Dataset Information

Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration.

Publications

Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration.

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