Decreased cortical Nrf2 gene expression in autism and its relationship to thiol and cobalamin status

Schrier, Matthew; Zhang, Yiting; Trivedi, Malav Suchin; Deth, Richard C.

doi:10.1016/j.biochi.2021.09.006

Cited by 18 publications

(8 citation statements)

References 135 publications

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“…Some studies of BTBR mice (a model of ASD) indicated that the Nrf2 system plays an important role in the regulation of neuroinflammation and oxidative stress in the brain (229,270). A study in monocytes from people with ASD found a positive result by regulating the Nrf2 system in an in vitro LPSinduced inflammatory model (271) and many other studies have reported the abnormalities of the Nrf2 system in ASD individuals (272,273). Therefore, the Nrf2 system is one of the important ways of antioxidant therapy.…”

Section: Asd Treatment and Oxidative Stressmentioning

confidence: 99%

Oxidative Stress in Autism Spectrum Disorder—Current Progress of Mechanisms and Biomarkers

et al. 2022

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Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that has been diagnosed in an increasing number of children around the world. Existing data suggest that early diagnosis and intervention can improve ASD outcomes. However, the causes of ASD remain complex and unclear, and there are currently no clinical biomarkers for autism spectrum disorder. More mechanisms and biomarkers of autism have been found with the development of advanced technology such as mass spectrometry. Many recent studies have found a link between ASD and elevated oxidative stress, which may play a role in its development. ASD is caused by oxidative stress in several ways, including protein post-translational changes (e.g., carbonylation), abnormal metabolism (e.g., lipid peroxidation), and toxic buildup [e.g., reactive oxygen species (ROS)]. To detect elevated oxidative stress in ASD, various biomarkers have been developed and employed. This article summarizes recent studies about the mechanisms and biomarkers of oxidative stress. Potential biomarkers identified in this study could be used for early diagnosis and evaluation of ASD intervention, as well as to inform and target ASD pharmacological or nutritional treatment interventions.

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Section: Asd Treatment and Oxidative Stressmentioning

confidence: 99%

Oxidative Stress in Autism Spectrum Disorder—Current Progress of Mechanisms and Biomarkers

et al. 2022

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“…This could be due to defective Nrf2 signaling in ASD neutrophils. Previous reports have shown that ASD subjects have impairment in the translocation of Nrf2 from the cytoplasm to the nucleus, thus leading to diminished antioxidant response [ 26 , 40 , 62 ]. This was confirmed by using the Nrf2 activator sulforaphane, which achieved upregulation of Nrf2-mediated proteins such as Trx1 and TrxR1 with concomitant reduction in oxidative stress in ASD neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin 1 and Thioredoxin Reductase 1 Redox System Is Dysregulated in Neutrophils of Subjects with Autism: In Vitro Effects of Environmental Toxicant, Methylmercury

Alshehri,

Ahmad,

Albekairi

et al. 2023

Toxics

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Autism spectrum disorder (ASD) is a complex developmental disorder in children that results in abnormal communicative and verbal behaviors. Exposure to heavy metals plays a significant role in the pathogenesis or progression of ASD. Mercury compounds pose significant risk for the development of ASD as children are more exposed to environmental toxicants. Increased concentration of mercury compounds has been detected in different body fluids/tissues in ASD children, which suggests an association between mercury exposure and ASD. Thioredoxin1 (Trx1) and thioredoxin reductase1 (TrxR1) redox system plays a crucial role in detoxification of oxidants generated in different immune cells. However, the effect of methylmercury and the Nrf2 activator sulforaphane on the Trx1/TrxR1 antioxidant system in neutrophils of ASD subjects has not been studied previously. Therefore, this study examined the effect of methylmercury on Trx1/TrxR1 expression, TrxR activity, nitrotyrosine, and ROS in neutrophils of ASD and TDC subjects. Our study shows that Trx1/TrxR1 protein expression is dysregulated in ASD subjects as compared to the TDC group. Further, methylmercury treatment significantly inhibits the activity of TrxR in both ASD and TDC groups. Inhibition of TrxR by mercury is associated with upregulation of the Trx1 protein in TDC neutrophils but not in ASD neutrophils. Furthermore, ASD neutrophils have exaggerated ROS production after exposure to methylmercury, which is much greater in magnitude than TDC neutrophils. Sulforaphane reversed methylmercury-induced effects on neutrophils through Nrf2-mediated induction of the Trx1/TrxR1 system. These observations suggest that exposure to the environmental toxicant methylmercury may elevate systemic oxidative inflammation due to a dysregulated Trx1/TrxR1 redox system in the neutrophils of ASD subjects, which may play a role in the progression of ASD.

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“…Primers were selected from previously published papers ( [80][81][82][83][84][85][86], Table S1) and their accompanying probes were designed using the Integrated DNA Technologies' PrimerQuest Tool. All genes of interest were normalized to the nuclear gene B2M.…”

Section: Quantitative Real-time Pcr (Rt-qpcr)mentioning

confidence: 99%

Transmission Electron Microscopy Reveals Propionic Acid-induced Alterations to Mitochondrial Morphology in SH-SY5Y Cells

Buchanan¹,

Mahony²,

Bam³

et al. 2022

Preprint

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Mitochondrial dysregulation is implicated in numerous neurological disorders. Mitochondrial dynamics, including biogenesis, fusion and fission, are essential components of mitostasis which is modulated by complex regulatory mechanisms. Although expression studies are often used to investigate mitochondrial dynamics, these studies may be limited by the interdependent and temporal nature of mitostasis. Transmission electron microscopy (TEM) and cryogenic preparation methods provide a direct approach to examine mitochondrial ultrastructure in neurons. We investigated the utility of TEM to visualize mitochondrial morphological changes in SH-SY5Y cells treated with propionic acid (PPA). We examined whether morphological alterations were associated with differences in membrane potential or expression of biogenesis, fusion and fission genes. PPA induced a significant decrease in mitochondrial area (p<0.01 5mM), Feret's diameter and perimeter (p<0.05 5mM), and in area2 (p<0.05 3mM, p<0.01 5mM) – consistent with a shift towards fission. Morphological changes were not associated with significant differences in mitochondrial membrane potential. However, we observed decreased gene expression of NRF1 (p<0.01), TFAM (p<0.05), and STOML2 (p<0.0001). These data support a disruption of the balance in dynamics to preserve function under stress. This demonstrates the utility of TEM to provide insight into mitochondrial dynamics and function which can inform targeted mechanistic investigations into neuropathology.

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Decreased cortical Nrf2 gene expression in autism and its relationship to thiol and cobalamin status

Cited by 18 publications

References 135 publications

Oxidative Stress in Autism Spectrum Disorder—Current Progress of Mechanisms and Biomarkers

Oxidative Stress in Autism Spectrum Disorder—Current Progress of Mechanisms and Biomarkers

Thioredoxin 1 and Thioredoxin Reductase 1 Redox System Is Dysregulated in Neutrophils of Subjects with Autism: In Vitro Effects of Environmental Toxicant, Methylmercury

Transmission Electron Microscopy Reveals Propionic Acid-induced Alterations to Mitochondrial Morphology in SH-SY5Y Cells

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