The hypothesis to be examined in this project is that aging in the brain leads to enhanced oxidative changes in the plasma membrane proteins responsible for transporting Ca2+ into or out of nerve cells and the cumulative effect of such changes is a decrease in the transport function of these proteins. The neuronal plasma membrane Na+/Ca2+ exchanger and the (Ca2+ + Mg2+)-ATPase are the major systems responsible for maintaining the 10/4-fold gradient for Ca2+ across the neuronal membrane, and the kinetic properties of these systems change in membranes from aged rat brain. Both of these transport systems are sensitive to in vitro reactive oxygen species (ROS). The goals of this project are: (1) to characterize the effects of oxidative stress on neuronal Na+/Ca2+ exchanger and plasma membrane CaATPase activity, (2) to determine whether oxidative damage alters the activity and the structural properties of the exchanger and the ATPase in a manner similar to that observed in the aging brain membranes, (3) to identify the peptide domains within each of the neuronal membrane Ca2+ transporting proteins that are most susceptible to oxidation-induced alterations and determine whether similar alterations can be detected in these regions of the proteins in aged brain, and (4) to determine the effects of oxidative stress on the kinetics of turnover of the Ca2+ - transporting proteins in primary neuronal cell culture systems in which the regulation of [Ca2+]/i, intracellular pH, and the metabolic status of the cells can be monitored under the same conditions. The effects of in vitro exposure to photo-oxidizing as well as chemically-induced radical formation on synaptic membrane Ca2+ transport systems will be studied under conditions which will indicate whether the proteins themselves undergo oxidative modification. Highly sensitive microanalytical techniques will be used to identify the sites. The possible occurrence of such modifications with aging in brain neurons will be assessed, since chronic mild oxidative stress may contribute to the compromised neuronal function which develops in a large percentage of the aged population.
The final aim i s devoted to obtaining a more dynamic picture of the multiplicity of effects that oxidative stress can have on Ca2+-regulation in intact cells which have repair mechanisms for oxidative damage to proteins. It is known only too well that the aging process, whatever it is at the cellular and molecular levels, is a risk factor for many pathological conditions, one of the worst being dementia such as the late- onset form of Alzheimer's Disease. The proposed studies will contribute to our understanding of the role that oxidative stress may play in age- related alterations in neuronal function and to our assessment of the future potential that better prevention and/or management of such stresses can have in preserving cognitive abilities well into the later part of the human lifespan.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG012993-03
Application #
6234546
Study Section
Project Start
1997-08-15
Project End
1998-07-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Type
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Hewarathna, Asha; Dremina, Elena; Schöneich, Christian (2017) Inhibition and conformational change of SERCA3b induced by Bcl-2. Biochim Biophys Acta Proteins Proteom 1865:121-131
Schöneich, Christian (2016) Thiyl radicals and induction of protein degradation. Free Radic Res 50:143-9
Poole, Leslie B; Schöneich, Christian (2015) Introduction: What we do and do not know regarding redox processes of thiols in signaling pathways. Free Radic Biol Med 80:145-7
Nauser, Thomas; Koppenol, Willem H; Schöneich, Christian (2015) Protein thiyl radical reactions and product formation: a kinetic simulation. Free Radic Biol Med 80:158-63
Badawi, Yomna; Pal, Ranu; Hui, Dongwei et al. (2015) Ischemic tolerance in an in vivo model of glutamate preconditioning. J Neurosci Res 93:623-32
Wang, Xinkun; Patel, Nilam D; Hui, Dongwei et al. (2014) Gene expression patterns in the hippocampus during the development and aging of Glud1 (Glutamate Dehydrogenase 1) transgenic and wild type mice. BMC Neurosci 15:37
Jiang, Lei; Bechtel, Misty D; Bean, Jennifer L et al. (2014) Effects of gangliosides on the activity of the plasma membrane Ca2+-ATPase. Biochim Biophys Acta 1838:1255-65
Schöneich, Christian; Dremina, Elena; Galeva, Nadezhda et al. (2014) Apoptosis in differentiating C2C12 muscle cells selectively targets Bcl-2-deficient myotubes. Apoptosis 19:42-57
Wang, Shu-Lin; Sun, Liuchao; Fang, Jianwen (2014) Molecular cancer classification using a meta-sample-based regularized robust coding method. BMC Bioinformatics 15 Suppl 15:S2
Choi, In-Young; Lee, Phil; Wang, Wen-Tung et al. (2014) Metabolism changes during aging in the hippocampus and striatum of glud1 (glutamate dehydrogenase 1) transgenic mice. Neurochem Res 39:446-55

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