Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

ABSTRACT

Many neurological conditions exhibit synaptic impairments, suggesting mechanistic convergence. Additionally, the pannexin 1 (PANX1) channel and signaling scaffold is linked to several of these neurological conditions and is an emerging regulator of synaptic development and plasticity; however, its synaptic pathogenic contributions are relatively unexplored. To this end, we explored connections between synaptic neurodevelopmental disorder and neurodegenerative disease susceptibility genes discovered by genome-wide association studies (GWASs), and the neural PANX1 interactome (483 proteins) identified from mouse Neuro2a (N2a) cells. To identify shared susceptibility genes, we compared synaptic suggestive GWAS candidate genes amongst autism spectrum disorders, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. To further probe PANX1 signaling pathways at the synapse, we used bioinformatics tools to identify PANX1 interactome signaling pathways and protein–protein interaction clusters. To shed light on synaptic disease mechanisms potentially linking PANX1 and these four neurological conditions, we performed additional cross-analyses between gene ontologies enriched for the PANX1 synaptic and disease-susceptibility gene sets. Finally, to explore the regional specificity of synaptic PANX1-neurological condition connections, we identified brain region-specific elevations of synaptic PANX1 interactome and GWAS candidate gene set transcripts. Our results confirm considerable overlap in risk genes for autism spectrum disorders and schizophrenia and identify potential commonalities in genetic susceptibility for neurodevelopmental disorders and neurodegenerative diseases. Our findings also pinpointed novel putative PANX1 links to synaptic disease-associated pathways, such as regulation of vesicular trafficking and proteostasis, warranting further validation.

KEYWORDS:

• PANX1
• neurodevelopment
• neurodegeneration
• synapse
• proteomics
• gene ontology

Acknowledgments

Additionally, the authors are grateful to Juan C. Sanchez-Arias for his initial input on the study design and discussion for the first bioRxiv preprint version of this work (posted October 11, 2019). LAS and SDF designed the study with inputs from LEWS. LEWS identified the PANX1 interactome in mouse N2a cells, SDF performed the bioinformatics analyses, and SDF, LEWS, and LAS wrote the manuscript. All authors approved the final manuscript. A preprint of this manuscript (prior to final peer review edits) can be found on bioRxiv: https://www.biorxiv.org/content/10.1101/801563v3.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Information about the publicly available data used in this study is outlined throughout the manuscript and supplemental tables. For the proteomics data, RAW files are deposited in the Center for Computational Mass Spectrometry (MassIVE MSV000093036). Please contact Dr. Leigh Anne Swayne ([email protected]) for additional information, if required. The R code is available and can be obtained from Dr. Simona Denise Frederiksen, upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19336950.2023.2253102

Additional information

Funding

This project was supported by operating grants from the Canadian Institutes of Health Research [MOP142215], the Natural Sciences and Engineering Research Council of Canada [NSERC; 402270-2011], and the University of Victoria Division of Medical Sciences to LAS. LAS was also supported by a Michael Smith Foundation for Health Research and British Columbia Schizophrenia Society Foundation Scholar Award [5900]. LEWS was supported by a Vanier Canada Graduate Scholarship (NSERC).