The Autistic Phenotype Exhibits a Remarkably Localized Modification of Brain Protein by Products of Free Radical-Induced Lipid Oxidation

Abstract

Abstract: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 iso [4]levuglandin (iso[4]LG)E 2 -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 ± 57.9 versus 110.4 ± 30.3 pmol/mL), iso [4]LGE 2 protein adducts (16.7 ± 5.8 versus 13.4 ± 3.4 nmol/mL), anti-CEP (1.2 ± 0.7 versus 1.2 ± 0.3) and anti-iso [4]LGE 2 autoantibody titre (1.3 ± 1.6 versus 1.0 ± 0.9), and no differences between the ratio of NO 2 Tyr/Tyr (7.81 E-06 ± 3.29 E-06 versus 7.87 E-06 ± 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.

Polyunsaturated phospholipids promote the oxidation and fragmentation of γ-hydroxyalkenals: formation and reactions of oxidatively truncated ether phospholipids

“…This may contribute to the occurrence of lipid-derived protein modifications in the brain. Thus, we recently reported that, remarkably, localized CEP and iso [4]levuglandin E 2 -derived protein modifications, which appear as filaments in the cortical tissue, are a hallmark of the autistic brain (43). Of course, a low level of PUFAs can also result in little or no susceptibility to oxidative damage, as PUFAs are the targets of free radical-induced lipid oxidation.…”

Isolevuglandin Adducts in Disease

“…Children born prematurely have significantly ( p = 0.008) elevated mean levels of blood plasma iso [4]LGE 2 -adduct immunoreactivity, 22.7 -5.9 nmol/ml (n = 6) compared with 15.3 -5.0 nmol/ml (n = 16) in children with no significant birth events (24). This suggests that chronic inflammation is a heretofore-unrecognized consequence of premature birth or postnatal treatment protocols that result in a failure to develop fully competent antioxidant defenses.…”

Characterization of the Pathological and Biochemical Markers that Correlate to the Clinical Features of Autism: The Neuropathological Markers of Abnormal Brain Development and Aging in Autism

“…Recent studies with the postmortem brain samples from autism and control subjects have provided further evidence on increased oxidative stress in autism. Increased levels of lipid-derived oxidative protein modifi cations, i.e., carboxyethylpyrrole and iso [4]levuglandin E 2 -protein adducts, and heme-oxygenase-1 (an inducible antioxidant enzyme) have been reported in the autistic brain, primarily in the white matter (Evans et al, 2008). Sajdel-Sulkowska et al (2008) have reported elevated levels of 3-nitrotyrosine (a specifi c marker for oxidative damage to proteins) in the cerebella of subjects with autism.…”