Impaired synthesis and antioxidant defense of glutathione in the cerebellum of autistic subjects: Alterations in the activities and protein expression of glutathione-related enzymes

Gu, Feng; Chauhan, Ved; Chauhan, Abha

doi:10.1016/j.freeradbiomed.2013.07.021

Cited by 76 publications

(51 citation statements)

References 86 publications

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“…Post-mortem analyses have more directly demonstrated abnormalities in enzymes involved in redox homeostasis and have identified evidence of oxidative damage to proteins, lipids, and DNA within the autistic brain [31, 62, 78, 80]. For instance, decreased MnSOD activity and increased 8-hydroxy-2′-deoxyguanosine, a marker of oxidatively modified DNA, were identified in Brodmann area 21 within the temporal lobe of autistic subjects [31].…”

Section: Alternative Mechanisms Of Asd Pathogenesismentioning

confidence: 99%

“…For instance, decreased MnSOD activity and increased 8-hydroxy-2′-deoxyguanosine, a marker of oxidatively modified DNA, were identified in Brodmann area 21 within the temporal lobe of autistic subjects [31]. Gu et al found decreased activity of glutathione peroxidase, glutathione-S-transferase, and glutamate cysteine ligase in the ASD cerebellum [80]. In addition, investigators have demonstrated decreased levels of reduced GSH, increased levels of GSSG, and lower GSH/GSSG ratios in the cerebellum, temporal lobe, and Brodmann area 22 of individuals with ASD [81, 82].…”

Section: Alternative Mechanisms Of Asd Pathogenesismentioning

confidence: 99%

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Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms

Griffiths

Levy

2017

Oxidative Medicine and Cellular Longevity

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Autism spectrum disorder (ASD), the fastest growing developmental disability in the United States, represents a group of neurodevelopmental disorders characterized by impaired social interaction and communication as well as restricted and repetitive behavior. The underlying cause of autism is unknown and therapy is currently limited to targeting behavioral abnormalities. Emerging studies suggest a link between mitochondrial dysfunction and ASD. Here, we review the evidence demonstrating this potential connection. We focus specifically on biochemical links, genetic-based associations, non-energy related mechanisms, and novel therapeutic strategies.

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Section: Alternative Mechanisms Of Asd Pathogenesismentioning

confidence: 99%

Section: Alternative Mechanisms Of Asd Pathogenesismentioning

confidence: 99%

Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms

Griffiths

Levy

2017

Oxidative Medicine and Cellular Longevity

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“…1 Although the cause of autism is elusive, numerous studies suggest that enhanced oxidative stress is a prevalent biochemical condition in autism. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 A recent meta-analysis study showed prevalence of mitochondrial disorder (MD) in the ASD population to be 5%, which is much higher than observed in general population (∼0.01%). 12 …”

Section: Introductionmentioning

confidence: 99%

Alterations in mitochondrial DNA copy number and the activities of electron transport chain complexes and pyruvate dehydrogenase in the frontal cortex from subjects with autism

et al. 2013

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Autism is a neurodevelopmental disorder associated with social deficits and behavioral abnormalities. Recent evidence suggests that mitochondrial dysfunction and oxidative stress may contribute to the etiology of autism. This is the first study to compare the activities of mitochondrial electron transport chain (ETC) complexes (I–V) and pyruvate dehydrogenase (PDH), as well as mitochondrial DNA (mtDNA) copy number in the frontal cortex tissues from autistic and age-matched control subjects. The activities of complexes I, V and PDH were most affected in autism (n=14) being significantly reduced by 31%, 36% and 35%, respectively. When 99% confidence interval (CI) of control group was taken as a reference range, impaired activities of complexes I, III and V were observed in 43%, 29% and 43% of autistic subjects, respectively. Reduced activities of all five ETC complexes were observed in 14% of autistic cases, and the activities of multiple complexes were decreased in 29% of autistic subjects. These results suggest that defects in complexes I and III (sites of mitochondrial free radical generation) and complex V (adenosine triphosphate synthase) are more prevalent in autism. PDH activity was also reduced in 57% of autistic subjects. The ratios of mtDNA of three mitochondrial genes ND1, ND4 and Cyt B (that encode for subunits of complexes I and III) to nuclear DNA were significantly increased in autism, suggesting a higher mtDNA copy number in autism. Compared with the 95% CI of the control group, 44% of autistic children showed higher copy numbers of all three mitochondrial genes examined. Furthermore, ND4 and Cyt B deletions were observed in 44% and 33% of autistic children, respectively. This study indicates that autism is associated with mitochondrial dysfunction in the brain.

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“…Significant decreases in reduced glutathione and increases in oxidized glutathione were detected in the cerebellum and temporal cortex from subjects with autism [49]. It has also been shown that the activity of glutathione peroxidase and glutathione-S-transferase enzymes as well as glutamate cysteine ligase, the rate limiting enzyme for glutathione synthesis decreased in cerebellar tissue of autistic patients [50]. Glutathione depletion plays important role in several neuropathological disease states e.g., Parkinson's disease, schizophrenia, and major depression and replenishing cellular glutathione have been advocated as a therapeutic approach in these conditions [19] [51] [52].…”

Section: Discussionmentioning

confidence: 98%

Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children

Abdel-Salam¹,

Youness²,

Mohammed³

et al. 2015

OJMIP

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The aim of the present study was to investigate the status of oxidative stress in the serum of children affected with autism spectrum disorder. Twenty autistic children aged 3 to 12 years, were gender and age-matched with 20 typically developing children. Changes in the levels of the redox-sensing transcription factor nuclear factor-kappa B (NF-κB) was measured in serum of autistic children and controls. Other oxidative stress biomarkers such as malondialdehyde, reduced glutathione, total antioxidant capacity, catalase activity, and paraoxonase 1 activity were determined in serum as well. Significant increase was observed in serum NF-κB of autistic children compared to that in controls (by 138.6%). There was also marked increase in malondialdehyde level by 87.3% in autistic patients. Meanwhile, there were significant decreases in reduced glutathione (by 24%), catalase activity (by 40.8%), paraoxonase 1 activity (by 36.6%), and total antioxidant capacity (by 36.5%) compared to the control group. These data clearly demonstrate increased oxidative stress in serum of autistic children and suggest that the NF-κB signaling pathway is activated in autism, possibly due to increased oxidative burden.

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Impaired synthesis and antioxidant defense of glutathione in the cerebellum of autistic subjects: Alterations in the activities and protein expression of glutathione-related enzymes

Cited by 76 publications

References 86 publications

Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms

Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms

Alterations in mitochondrial DNA copy number and the activities of electron transport chain complexes and pyruvate dehydrogenase in the frontal cortex from subjects with autism

Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children

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