Regional Differences in S-Nitrosylation in the Cortex, Striatum, and Hippocampus of Juvenile Male Mice

Hamoudi, Wajeha; Lendenfeld, Felix von; Kartawy, Maryam; Mencer, Shira; Suloh, Huda; Khaliulin, Igor; Amal, Haitham

doi:10.1007/s12031-021-01792-z

Cited by 10 publications

(5 citation statements)

References 52 publications

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“…SNO is a reversible NO-mediated posttranslational modification of cysteine thiols of proteins that modulate cell signaling pathways, neuronal functions, and synaptic plasticity [ 29 , 30 , 33 , 37 – 41 ]. SNO occurs in different neuroanatomical regions, including the cortex, hippocampus, and striatum [ 42 ]. It contributes to multiple physiological and neuropathological processes.…”

Section: Discussionmentioning

confidence: 99%

Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

et al. 2021

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Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are two different neurological disorders that share common clinical features, such as language impairment, executive functions, and motor problems. A genetic convergence has been proposed as well. However, the molecular mechanisms of these pathologies are still not well understood. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the InsG3680(+/+) ASD and P301S AD mouse models. Here, we performed large-scale computational biology analysis of the SNO-proteome followed by biochemical validation to decipher the shared mechanisms between the pathologies. This analysis pointed to the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as one of the shared molecular mechanisms. Activation of mTOR in the cortex of both mouse models was confirmed by western blots that showed increased phosphorylation of RPS6, a major substrate of mTORC1. Other molecular alterations affected by SNO and shared between the two mouse models, such as synaptic-associated processes, PKA signaling, and cytoskeleton-related processes were also detected. This is the first study to decipher the SNO-related shared mechanisms between SHANK3 and MAPT mutations. Understanding the involvement of SNO in neurological disorders and its intersection between ASD and AD might help developing an effective novel therapy for both neuropathologies.

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Section: Discussionmentioning

confidence: 99%

Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

et al. 2021

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“…[25,29] However, the etiology of ASD remains elusive. [30,31] Recently, we found elevated levels of nitric oxide (NO) in an ASD mouse model; [32][33][34][35] we suggested several mechanisms for the involvement of NO, S-nitrosylation (SNO), and NO-mediated posttranslational modification (PTM) in ASD pathology. [32,33,[36][37][38][39] NO is a small gaseous molecule produced in different organs and tissues, including the central [40] and peripheral nervous systems.…”

Section: Introductionmentioning

confidence: 98%

“…Recently, we found elevated levels of nitric oxide (NO) in an ASD mouse model; [ 32–35 ] we suggested several mechanisms for the involvement of NO, S‐nitrosylation (SNO), and NO‐mediated posttranslational modification (PTM) in ASD pathology. [ 32,33,36–39 ]…”

Section: Introductionmentioning

confidence: 99%

The NO Answer for Autism Spectrum Disorder

et al. 2023

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Autism spectrum disorders (ASDs) include a wide range of neurodevelopmental disorders. Several reports showed that mutations in different high-risk ASD genes lead to ASD. However, the underlying molecular mechanisms have not been deciphered. Recently, they reported a dramatic increase in nitric oxide (NO) levels in ASD mouse models. Here, they conducted a multidisciplinary study to investigate the role of NO in ASD. High levels of nitrosative stress biomarkers are found in both the Shank3 and Cntnap2 ASD mouse models. Pharmacological intervention with a neuronal NO synthase (nNOS) inhibitor in both models led to a reversal of the molecular, synaptic, and behavioral ASD-associated phenotypes. Importantly, treating iPSC-derived cortical neurons from patients with SHANK3 mutation with the nNOS inhibitor showed similar therapeutic effects. Clinically, they found a significant increase in nitrosative stress biomarkers in the plasma of low-functioning ASD patients. Bioinformatics of the SNO-proteome revealed that the complement system is enriched in ASD. This novel work reveals, for the first time, that NO plays a significant role in ASD. Their important findings will open novel directions to examine NO in diverse mutations on the spectrum as well as in other neurodevelopmental disorders. Finally, it suggests a novel strategy for effectively treating ASD.

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“…SNO is a reversible NO-mediated post-translational modification of cysteine thiols of the proteins and peptides in which cysteine is converted to nitrosothiol [ 3 , 16 ]. SNO plays a major role in the localization and activity of a wide range of key enzymes and receptors in physiological and pathological conditions, leading to modulation of many signaling pathways, axonal transport, synaptic plasticity, and protein assembly [ 3 , 16 , 18 , 19 , 20 ]. Aberrant SNO signaling may contribute to the progression of many neurodegenerative [ 21 , 22 , 23 , 24 ], neurodevelopmental [ 3 , 16 ], and neuropsychiatric disorders [ 16 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Systems Biology Reveals S-Nitrosylation-Dependent Regulation of Mitochondrial Functions in Mice with Shank3 Mutation Associated with Autism Spectrum Disorder

2021

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder manifested in repetitive behavior, abnormalities in social interactions, and communication. The pathogenesis of this disorder is not clear, and no effective treatment is currently available. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the ASD mouse model based on the Shank3 mutation. The energy supply to the brain mostly relies on oxidative phosphorylation in the mitochondria. Recent studies show that mitochondrial dysfunction and oxidative stress are involved in ASD pathology. In this work, we performed SNO proteomics analysis of cortical tissues of the Shank3 mouse model of ASD with the focus on mitochondrial proteins and processes. The study was based on the SNOTRAP technology followed by systems biology analysis. This work revealed that 63 mitochondrial proteins were S-nitrosylated and that several mitochondria-related processes, including those associated with oxidative phosphorylation, oxidative stress, and apoptosis, were enriched. This study implies that aberrant SNO signaling induced by the Shank3 mutation can target a wide range of mitochondria-related proteins and processes that may contribute to the ASD pathology. It is the first study to investigate the role of NO-dependent mitochondrial functions in ASD.

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Regional Differences in S-Nitrosylation in the Cortex, Striatum, and Hippocampus of Juvenile Male Mice

Cited by 10 publications

References 52 publications

Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

The NO Answer for Autism Spectrum Disorder

Systems Biology Reveals S-Nitrosylation-Dependent Regulation of Mitochondrial Functions in Mice with Shank3 Mutation Associated with Autism Spectrum Disorder

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