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Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function

Molecular Psychiatry volume 25, pages 1835–1848 (2020)Cite this article

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Abstract

Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan-McDermid syndrome. Shank3 disruption in mice leads to dysfunction of synaptic transmission, behavior, and development. Protein S-nitrosylation, the nitric oxide (NO•)-mediated posttranslational modification (PTM) of cysteine thiols (SNO), modulates the activity of proteins that regulate key signaling pathways. We tested the hypothesis that Shank3 mutation would generate downstream effects on PTM of critical proteins that lead to modification of synaptic functions. SNO-proteins in two ASD-related brain regions, cortex and striatum of young and adult InsG3680(+/+) mice (a human mutation-based Shank3 mouse model), were identified by an innovative mass spectrometric method, SNOTRAP. We found changes of the SNO-proteome in the mutant compared to WT in both ages. Pathway analysis showed enrichment of processes affected in ASD. SNO-Calcineurin in mutant led to a significant increase of phosphorylated Synapsin1 and CREB, which affect synaptic vesicle mobilization and gene transcription, respectively. A significant increase of 3-nitrotyrosine was found in the cortical regions of the adult mutant, signaling both oxidative and nitrosative stress. Neuronal NO• Synthase (nNOS) was examined for levels and localization in neurons and no significant difference was found in WT vs. mutant. S-nitrosoglutathione concentrations were higher in mutant mice compared to WT. This is the first study on NO•-related molecular changes and SNO-signaling in the brain of an ASD mouse model that allows the characterization and identification of key proteins, cellular pathways, and neurobiological mechanisms that might be affected in ASD.

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Acknowledgements

This work was supported by the MIT Center for Environmental Health Sciences Grant ES002109 and a grant from the Simons Foundation to the Simons Center for the Social Brain at MIT (SRT). Dr. Haitham Amal was supported by the Satell Technion-MIT Post-Doctoral Program. Research related to this project in the Feng lab was supported by NIMH (MH097104), Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, Nancy Lurie Marks Family Foundation and Simons Center for the Social Brain at MIT. Dr. Boaz Barak was supported by postdoctoral fellowships from the Simons Center for the Social Brain at MIT and the Autism Science Foundation. Brian Joughin was supported by Army Research Office Institute for Collaborative Biotechnologies grant W911NF-09-0001.

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Author notes

  1. These authors contributed equally: Haitham Amal, Boaz Barak.

Authors and Affiliations

  1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Haitham Amal, Guanyu Gong, Brian A. Joughin, Xin Wang, John S. Wishnok & Steven R. Tannenbaum

  2. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Boaz Barak & Guoping Feng

  3. Agilent Tech. Inc, Wilmington, DE, 19808, USA

    Vadiraja Bhat

  4. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Brian A. Joughin

  5. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Steven R. Tannenbaum

Authors
  1. Haitham Amal
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  2. Boaz Barak
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  3. Vadiraja Bhat
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  4. Guanyu Gong
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  5. Brian A. Joughin
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  6. Xin Wang
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  7. John S. Wishnok
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  8. Guoping Feng
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  9. Steven R. Tannenbaum
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Corresponding authors

Correspondence to Haitham Amal or Steven R. Tannenbaum.

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Supplementary Information

Plots of the number of proteins identified for each subset of 6 replicates

SNO-protein interactomes of InsG3680(+/+) groups

SNO-protein interactomes of WT groups

41380_2018_113_MOESM5_ESM.tif

Lists of proteins in 6w-cor-KO and 4m-cor-KO that were clustered in String and are functioning in processes known to be correlated with ASD

Venn diagrams comparing 6w-old and 4m-old mice

Ntyr staining intensity of cortical and striatal regions in 6 week-old mice

Ntyr staining intensity of cortical and striatal regions in 4 month-old mice

Nitrotyrosine IHC staining

nNOS levels quantification

Lists of SNO-proteins of the tested groups and of the overlap between the WT and InsG3680(+/+) groups

Lists of GO and KEGG terms of the tested groups

41380_2018_113_MOESM13_ESM.xlsx

Lists of proteins that were enriched in important pathways and processes and are found in cor-KO groups, not in cor-WT groups

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Amal, H., Barak, B., Bhat, V. et al. Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function. Mol Psychiatry 25, 1835–1848 (2020). https://doi.org/10.1038/s41380-018-0113-6

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  • DOI: https://doi.org/10.1038/s41380-018-0113-6

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