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Systematic Analysis of Protein–Protein and Gene–Environment Interactions to Decipher the Cognitive Mechanisms of Autism Spectrum Disorder

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Abstract

Autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder resulting from both genetic and environmental risk factors, is manifested by deficits in cognitive function. Elucidating the cognitive disorder-relevant biological mechanisms may open up promising therapeutic approaches. In this work, we mined ASD cognitive phenotype proteins to construct and analyze protein–protein and gene–environment interaction networks. Incorporating the protein–protein interaction (PPI), human cognition proteins, and connections of autism-cognition proteins enabled us to generate an autism-cognition network (ACN). With the topological analysis of ACN, important proteins, highly clustered modules, and 3-node motifs were identified. Moreover, the impact of environmental exposures in cognitive impairment was investigated through chemicals that target the cognition-related proteins. Functional enrichment analysis of the ACN-associated modules and chemical targets revealed biological processes involved in the cognitive deficits of ASD. Among the 17 identified hub-bottlenecks in the ACN, PSD-95 was recognized as an important protein through analyzing the module and motif interactions. PSD-95 and its interacting partners constructed a cognitive-specific module. This hub-bottleneck interacted with the 89 cognition-related 3-node motifs. The identification of gene–environment interactions indicated that most of the cognitive-related proteins interact with bisphenol A (BPA) and valproic acid (VPA). Moreover, we detected significant expression changes of 56 cognitive-specific genes using four ASD microarray datasets in the GEO database, including GSE28521, GSE26415, GSE18123 and GSE29691. Our outcomes suggest future endeavors for dissecting the PSD-95 function in ASD and evaluating the various environmental conditions to discover possible mechanisms of the different levels of cognitive impairment.

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Acknowledgements

The authors gratefully acknowledge the support of the Shahid Beheshti University of Medical Sciences.

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Authors and Affiliations

  1. Proteomics Research Center, Shahid Beheshti University of Medical Sciences, 19716-53313, Tehran, Iran

    Masoumeh Farahani & Mona Zamanian-Azodi

  2. Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, 19716-53313, Tehran, Iran

    Mostafa Rezaei-Tavirani

  3. Functional Neurosurgery Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Alireza Zali

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  1. Masoumeh Farahani
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  2. Mostafa Rezaei-Tavirani
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Correspondence to Mostafa Rezaei-Tavirani.

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Farahani, M., Rezaei-Tavirani, M., Zali, A. et al. Systematic Analysis of Protein–Protein and Gene–Environment Interactions to Decipher the Cognitive Mechanisms of Autism Spectrum Disorder. Cell Mol Neurobiol 42, 1091–1103 (2022). https://doi.org/10.1007/s10571-020-00998-w

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