Abstract
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.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early-onset deficits in social communication, repetitive behaviors, and restricted interests [1,2]
This was followed by systems biology analysis of the SNO proteins to dissect the biological processes (BP), molecular functions (MF), and cellular components (CC) that are enriched among the SNO proteins
The MF analysis of the SNO proteins demonstrated the enrichment of multiple molecular functions related to the mitochondria, such as electron transfer activity (FDR = 0.0223), ATPase activity (FDR = 1.90 × 10−5), adenosine triphosphate (ATP) binding (FDR = 1.82 × 10−10), and ATPase binding (FDR = 0.0316) (Figure 1B)
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early-onset deficits in social communication, repetitive behaviors, and restricted interests [1,2]. SHANK3 mutation is one of the most promising ASD-associated human mutations. We used the human mutation-based mouse model for ASD (InsG3680(+/+)), in which a guanine nucleotide was inserted at cDNA position 3680 of the Shank gene, leading to a frameshift that resulted in a premature stop codon. These mice were shown to have striatal and cortico-striatal synaptic transmission and social behavioral defects, along with intense overgrooming and repetitive behavior [5]
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