The Autistic Phenotype Exhibits a Remarkably Localized Modification of Brain Protein by Products of Free Radical-Induced Lipid Oxidation
Teresa A. Evans, Sandra L. Siedlak, Liang Lu, Xiaoming Fu, Zeneng Wang, Woody R. McGinnis, Evelyn Fakhoury, Rudy J. Castellani, Stanley L. Hazen, William J. Walsh, Allen T. Lewis, Robert G. Salomon, Mark A. Smith, George Perry and Xiongwei Zhu
DOI : 10.3844/ajbbsp.2008.61.72
American Journal of Biochemistry and Biotechnology
Volume 4, Issue 2
Oxidative damage has been documented in the peripheral tissues of autism patients. In this study, we sought evidence of oxidative injury in autistic brain. Carboxyethyl pyrrole (CEP) and isolevuglandin (isoLG)E2-protein adducts, that are uniquely generated through peroxidation of docosahexaenoate and arachidonate-containing lipids respectively, and heme oxygenase-1 were detected immunocytochemically in cortical brain tissues and by ELISA in blood plasma. Significant immunoreactivity toward all three of these markers of oxidative damage in the white matter and often extending well into the grey matter of axons was found in every case of autism examined. This striking threadlike pattern appears to be a hallmark of the autistic brain as it was not seen in any control brain, young or aged, used as controls for the oxidative assays. Western blot and immunoprecipitation analysis confirmed neurofilament heavy chain to be a major target of CEP-modification. In contrast, in plasma from 27 autism spectrum disorder patients and 11 age-matched healthy controls we found similar levels of plasma CEP (124.5 Â± 57.9 versus 110.4 Â± 30.3 pmol/mL), isoLGE2 protein adducts (16.7 Â± 5.8 versus 13.4 Â± 3.4 nmol/mL), anti-CEP (1.2 Â± 0.7 versus 1.2 Â± 0.3) and anti-isoLGE2 autoantibody titre (1.3 Â± 1.6 versus 1.0 Â± 0.9), and no differences between the ratio of NO2Tyr/Tyr (7.81 E-06 Â± 3.29 E-06 versus 7.87 E-06 Â± 1.62 E-06). These findings provide the first direct evidence of increased oxidative stress in the autistic brain. It seems likely that oxidative injury of proteins in the brain would be associated with neurological abnormalities and provide a cellular basis at the root of autism spectrum disorders.
© 2008 Teresa A. Evans, Sandra L. Siedlak, Liang Lu, Xiaoming Fu, Zeneng Wang, Woody R. McGinnis, Evelyn Fakhoury, Rudy J. Castellani, Stanley L. Hazen, William J. Walsh, Allen T. Lewis, Robert G. Salomon, Mark A. Smith, George Perry and Xiongwei Zhu. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.