Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 90, Issue 6, Pages 1230-1239Publisher
WILEY
DOI: 10.1002/jnr.23018
Keywords
APE1; Ref-1; AP endonuclease 1; ss; amyloid; neuroprotection; base excision repair; neurodegeneration; oxidative DNA damage
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Funding
- USPHS [RO1 CA53791, RO1 ES08457, P30 ES006676]
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The genotoxic, extracellular accumulation of amyloid beta (A beta) protein and subsequent neuronal cell death are associated with Alzheimer's disease (AD). APE1/Ref-1, the predominant apurinic/apyrimidinic (AP) endonuclease and essential in eukaryotic cells, plays a central role in the base excision repair (BER) pathway for repairing oxidized and alkylated bases and single-strand breaks (SSBs) in DNA. APE1/Ref-1 is also involved in the redox activation of several trans-acting factors (TFs) in various cell types, but little is known about its role in neuronal functions. There is emerging evidence for APE1/Ref-1's role in neuronal cells vulnerable in AD and other neurodegenerative disorders, as reflected in its nuclear accumulation in AD brains. An increase in APE1/Ref-1 has been shown to enhance neuronal survival after oxidative stress. To address whether APE1/Ref-1 level or its association with other proteins is responsible for this protective effect, we used 2-D proteomic analyses and identified cytoskeleton elements (i.e., tropomodulin 3, tropomyosin alpha-3 chain), enzymes involved in energy metabolism (i.e., pyruvate kinase M2, N-acetyl transferase, sulfotransferase 1c), proteins involved in stress response (i.e., leucine-rich and death domain, anti-NGF30), and heterogeneous nuclear ribonucleoprotien-H (hnRNP-H) as being associated with APE1/Ref-1 in A beta(2535)-treated rat pheochromocytoma PC12 and human neuroblastoma SH-SY5Y cell lines, two common neuronal precursor lines used in A beta neurotoxicity studies. Because the levels of some of these proteins are affected in the brains of AD patients, our study suggests a neuroprotective role for APE1/Ref-1 via its association with those proteins and modulating their cellular functions during A beta-mediated neurotoxicity. (c) 2012 Wiley Periodicals, Inc.
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