We are interested in a possible link between oxidative stress, aging and neurodegenerative diseases. In recent studies of adaptation to oxidative stress we have identified several previously unknown genes (in addition to confirming the overexpression of several known genes) that appear to provide stress protection in isolated hamster cells in culture. These """"""""adapt"""""""" genes include: adapt15, adapt33, adapt66, adapt73, adapt78, and adapt 116. Although our studies indicate that full adaptation depends upon both transcription and translation, it is not clear which genes are actually required. Although each of these newly discovered genes is worthy of detailed study, adapt78 whose mRNA levels increase more than 50 fold in adaptation, in particular stands out. In screening studies employing autopsy samples from human brains, we have now found that the human homologue of adapt78 exhibits extremely high levels of expression in brain autopsy samples from Alzheimer's disease patients, and low levels of expression in brain samples encompassing the substantia nigra from patients who died with Parkinson's disease. Recently, it has become clear that our adapt78 is identical to (or at least highly homologous with) the simultaneously independently discovered Down syndrome critical region 1 (DSCR1) gene of chromosome 21. Furthermore, two different isoforms of both adapt78 and DSCR1 are differentially expressed; corresponding to differentially spliced forms of exons 1-5, 6, 7 and exons 4-5, 6, 7. We propose to now carefully study expression of both isoforms of the human adapt78 gene in different brain regions, using the more sensitive techniques of RT-PCR and in situ hybridization. We plan to study adapt78 expression as a function of age, in brain autopsy samples from otherwise healthy individuals, since adapt78 expression may well vary with age. We will perform detailed studies of brain samples from Alzheimer's disease patients, Parkinson's disease patients, and Down syndrome patients in order to carefully determine both qualitative and quantitative differences in expression of both isoforms of adapt78 mRNA. Localization of adapt78 mRNA expression by cell type will also be studied. We also will synthesize and characterize the (1-5, 6, 7 and 4-5, 6, 7) Adapt78 proteins and generate antibodies to them in order to study expression of the actual proteins in all cell and brain samples. In cell culture studies, with PC-12 cells, we will test the hypothesis that inducible overexpression of adapt78 may confer an oxidative stress resistance phenotype. We will also test the ability of inducible adapt78 overexpressing cells to overcome the lethal oxidizing effects of glutathione deficiency, caused by expression of antisense message to gamma glutamylcysteine synthetase. These studies will allow us to begin to investigate our hypothesis that aging, and perhaps certain neurodegenerative diseases, involving defects in the expression of adapt78 and other adaptive genes required to cope with the deleterious effects of oxidative stress.
| Cadet, Jean; Davies, Kelvin J A (2017) Oxidative DNA damage & repair: An introduction. Free Radic Biol Med 106:100-110 |
| Cadet, Jean; Davies, Kelvin J A (2017) Oxidative DNA damage & repair: An introduction. Free Radic Biol Med 107:2-12 |
| Raynes, Rachel; Pomatto, Laura C D; Davies, Kelvin J A (2016) Degradation of oxidized proteins by the proteasome: Distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways. Mol Aspects Med 50:41-55 |
| Davies, Kelvin J A (2016) Adaptive homeostasis. Mol Aspects Med 49:1-7 |
| Grimm, Stefanie; Hoehn, Annika; Davies, Kelvin J et al. (2011) Protein oxidative modifications in the ageing brain: consequence for the onset of neurodegenerative disease. Free Radic Res 45:73-88 |
| Ermak, Gennady; Pritchard, Melanie A; Dronjak, Sladjana et al. (2011) Do RCAN1 proteins link chronic stress with neurodegeneration? FASEB J 25:3306-11 |
| Lloret, Ana; Badia, Mari-Carmen; Giraldo, Esther et al. (2011) Amyloid-? toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease. J Alzheimers Dis 27:701-9 |
| Harris, Cathryn D; Ermak, Gennady; Davies, Kelvin J A (2007) RCAN1-1L is overexpressed in neurons of Alzheimer's disease patients. FEBS J 274:1715-24 |
| Ermak, Gennady; Harris, Cathryn D; Battocchio, Denis et al. (2006) RCAN1 (DSCR1 or Adapt78) stimulates expression of GSK-3beta. FEBS J 273:2100-9 |
| Harris, C D; Ermak, G; Davies, K J A (2005) Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product calcipressin 1 (or RCAN1) in disease. Cell Mol Life Sci 62:2477-86 |
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