Biomedical Sciences Graduate Program | University of California, San Francisco

Raymond A. Swanson, MD
Bioenergetics and cell death in the central nervous system

Selected Publications | Complete Publications

phone	(415) 750-2011
email	raymond.swanson@ucsf.edu
additional websites	Lab Website
secondary research affiliation	none

Cell death in the CNS has several unique features stemming from the special characteristics of excitable cells. I have a longstanding interest in excitotoxic and oxidative neuronal death, and in particular, the role of bioenergetics in these processes. A current focus of our work is the ubiquitous nuclear enzyme, poly(ADP-ribose polymerase-1 (PARP-1). PARP-1 is an enzyme that normally functions in DNA repair, but which also mediates bioenergetic failure during excitotoxic and oxidative cell death. PARP activation is also an important mediator of microglial activation, and hence brain inflammation, by virtue of its interaction with NF-?B. A major aim of our research program is to elucidate the bioenergetic events between activation of PARP and cell death under disease conditions in brain. A related question concerns the cellular origin of oxidative stress that activates PARP-1. Oxidant production in neurons is widely attributed to the mitochondria, but NADPH oxidase can be the major source of reactive oxidants under some conditions. NADPH oxidase requires glucose to regenerate NADPH substrate, thus forming another intriguing link to cell bioenergetics. A second source of oxidative stress is impaired oxidant scavenging. We have identified the "glutamate" transporter EAAT3 as the major route of neuronal cysteine uptake. Mice that lack EAAT3 have reduced glutathione levels in neurons and undergo age-dependent neurodegeneration and cognitive impairment. The dopaminergic neurons of the substantia nigra are particularly affected. These studies are germane to Parkinson's disease, ischemia, and other conditions in which oxidative stress contributes to neuronal demise.

Selected Publications

Ying W, Sevigny MB , Chen Y, Swanson RA : Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death. Proc Natl Acad Sci, 98:12227-12232, 2001

Anderson CM, Norquist BA, Vesce S, Nicholls DG, Soine WH, Duan S, Swanson RA: Barbiturates potentiate excitotoxicity by inhibiting mitochondrial respiration. J Neuroscience , 22:9203-9209, 2002

Garnier P, Ying W, Swanson RA : Ischemic preconditioning by caspase cleavage of Poly(ADP-ribose) polymerase-1. J Neuroscience 23:7967-7973, 2003

Suh SW, Aoyama K, Chen Y, Garnier P Matsumori Y, Gum E, Liu J, Swanson RA : Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia. J Neuroscience 23:10681-10690, 2003

Kauppinen TM, Swanson RA : Poly(ADP-ribose)polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9 - mediated neuron death. J Immunology , 15:2288-2296, 2005

Kauppinen TM, Suh SW, Wiggins AK, Huang EJ, Swanson RA : Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated proteins 1/2 . Proc Natl Acad Sci 103:7136-41, 2006

Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA : Neuron al glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nature Neuroscience , 9:119-126, 2006

Alano, CC, Kauppinen TM, Swanson RA : Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci 103:9685-90, 2006

Kauppinen TM, Higashi, Y, Suh SW, Escartin C, Nagasawa K, Swanson RA: Zinc triggers microglial activation. J Neuroscience 28:5827-35, 2007

Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA : Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest . 117:910-8. 2008

Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, Swanson RA: Glucose and NADPH oxidase drive neuronal superoxide production during ischemia-reperfusion. Annals of Neurology 64:654–663, 2008

Burns DM, Ying W, Kauppinen TM, Zhu K, Swanson RA: Selective Down-Regulation of Nuclear Poly(ADP-Ribose) Glycohydrolase. PLoS ONE, 4e4896, 2009

Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H, Edling Y, Chan PH, Swanson RA: NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nature Neuroscience, in press

information last updated September 2009