Free radicals, oxidative stress and the origin of Parkinson's disease.

In this issue, Ihara et al. [1] have contributed important They found decreases in PD blood of RBC SOD1 and observations to support the hypothesis that increased some increase in PD plasma SOD (total), the origin of oxidative stress is a primary causal event in the etiology of which was not clear from their assays of individual SOD Parkinson’s disease (PD). By adding the ESR hydroxyl isoform protein levels. Interestingly, treatment of PD with radical (OH*) spin trap DMPO to fresh blood samples, pergolide raised the depressed RBC SOD1 activity. If they documented more than a two-fold increase in ex vivo pergolide brings about similar changes in neurons, this OH* production in PD subjects compared to controls. OH* may explain its neuroprotective actions in animal models. production in PD blood samples was over 1.5 times that Many other mechanisms are also possible. found in subjects with multi-system atrophy (MSA), SOD’s form the first enzymatic line of defense against certainly a heterogeneous group whose underlying one of the more commonly formed and least toxic oxygen pathologies likely reflect more than one origin. PD blood free radicals, superoxide anion. Superoxide is believed to OH* production was not correlated with age, but was be the first ROS formed when electrons escape from the about 60% greater in those with early age of onset of otherwise tightly regulated electron transport chain and disease and increased about 40% if disease duration was combine with electrophilic oxygen molecules. The presgreater than 6 years. Commonly used dopamine-mimetic ence of SOD’s as both copper /zinc requiring /cytoplasmic drugs such as L-DOPA, pergolide or bromocriptine had no (CuZnSOD, SOD1) and manganese-requiring /mitochoneffect on OH* production. drial (MnSOD, SOD2) isoforms likely reflects the What happens to a cell if too much reactive oxygen evolutionary importance of removing superoxide efficientspecies (ROS) are around? All intracellular components ly from all intracellular compartments. A good reason for appear susceptible to oxidative damage, resulting in formaall this cellular concern about superoxide is the nontion of lipid peroxides in membranes, hydroxylated bases enzymatic reaction between superoxide and ubiquitously in DNA and RNA, and nitrosylated proteins. Which of present nitric oxide to yield peroxynitrite, one of the more these effects of ROS is more important to altering cell damaging ROS available in its own right, in addition to its survival is not yet clear, particularly for a neurodegeneraprecursor status for OH*, the most reactive and damaging tive disease that develops over years, but increasing ROS of all ROS known. Ironically, OH* is also available levels within cells is a predictable method of activating cell non-enzymatically from hydrogen peroxide, the product of death pathways. ROS can turn on the entire system, SOD action, if enough unbound ferrous iron is available. beginning with opening of mitochondrial transition pores So, removal of hydrogen peroxide after SOD action is also and proceeding through activation of caspases, cleavage of important to cells, and the catalase and glutathione perintracellular caspase targets and DNA fragmentation. oxidase systems have developed for this purpose. Ihara et al. also explored RBC and plasma activities and While the methodology of Ihara et al. does not provide protein levels of superoxide dismutases (SOD’s), enzymes insight into the cellular or organelle origin of the increased which change superoxide anion to hydrogen peroxide. OH* production in PD, recent experiments with cybrid technology suggest that abnormal mitochondria in PD can explain the increased oxidative stress they found in PD *Tel.: 11-804-924-8374; fax: 11-804-924-0370. E-mail address: bennett@virginia.edu (J.P. Bennett) blood. Cybrids, or ‘cytoplasmic hybrids’ are mitochondrial