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

Abstract

The Pannexin 1 (Panx1) channel-forming protein is enriched in the central nervous system, and has been associated with several critical neurodevelopmental and plasticity functions; these include dendritic spine formation, neuronal network development, synaptic plasticity, and pathological brain states such as ischemia, epilepsy, and neurodegeneration. Despite major advances in understanding the properties and activation modes of Panx1, the Panx1 interactome remains largely uncharacterized. Considering that Panx1 has been implicated in critical neurodevelopmental and neurodegenerative processes and diseases, we investigated the Panx1 interactome (482 Panx1interacting proteins) identified from mouse N2a cells. These proteins were cross-analyzed with the postsynaptic proteome of the adult mouse brain previously identified by mass spectrometry (LC-MS/MS), and neurodegenerative disease and neurodevelopmental disorder susceptibility genes previously identified by genome-wide association studies (GWAS); and then further investigated using various bioinformatics tools (PAN-THER, GO, KEGG and STRING databases). A total of 104 of the Panx1-interacting proteins were located at the postsynapse, and 99 of these formed a 16-cluster protein-protein interaction (PPI) network (hub proteins: Eef2, Rab6A, Ddx39b, Mapk1, Fh1, Ndufv1 et cetera). The cross-analysis led to the discovery of proteins and candidate genes involved in synaptic function and homeostasis. Of particular note, our analyses also revealed that certain Panx1-interacting proteins are implicated in Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, schizophrenia, autism spectrum disorder and epilepsy. Altogether, our work revealed important clues to the role of Panx1 in neuronal function in health and disease by expanding our knowledge of the PPI network of Panx1, and unveiling previously unidentified Panx1-interacting proteins and networks involved in biological processes and disease. Panx1 | PPIs | pathway analysis | neurodegenerative diseases | neurodevelopmental disorders | Parkinson disease | Alzheimer disease | chaperones | vesicle-mediated transportFunctional annotation, categorization and overrepresentation analyses of the Panx1 interactome using the PANTHER database. Bioinformatics analysis of all proteins in our Panx1-interacting protein list (using UniProt accession numbers) was carried out using the PANTHER database v14.1 (Mi et al., 2013;Thomas et al., 2003), which is a curated database that includes several bioinformatics tools. The proteins (or their corresponding genes, depending on the nature of the analysis) were annotated to (i) PAN-THER protein classes from the PANTHER protein class ontology, (ii) gene ontology (GO) terms within the biological process, molecular function and cellular component domains from the GO knowledge base and (iii) PANTHER pathways created using the CellDesigner tool, a modelling tool for biochemical networks (Funahashi et al., 2008;Mi et al., 2019a;Mi et al., 2013). Note that PANTHER pa...

Mitochondrial pannexin1 controls cardiac sensitivity to ischaemia/reperfusion injury

“… 44 Indeed, the previous proteomic analysis identified cytoskeletal proteins as well as mitochondrial proteins like VDAC1, ANT2, and heat shock protein 70 (Hsc70) as Panx1 partners. 34 , 44 , 46 Here, we demonstrated for the first time that Panx1 is present in the SSM of murine cardiomyocytes ( Figure 4 A and E ). Altered mitochondrial morphology has been reported in the setting of cardiac I/R (for a review, see Ref.…”