Bioinformatic Analyses of Canonical Pathways of TSPOAP1 and its Roles in Human Diseases

Abstract

TSPO-associated protein 1 (TSPOAP1) is a cytoplasmic protein and is closely associated with its mitochondrial transmembrane protein partner translocator protein (TSPO). To decipher the canonical signalling pathways of TSPOAP1, its role in human diseases and disorders, and relationship with TSPO; expression analyses of TSPOAP1- and TSPO-associated human genes were performed by Qiagen Ingenuity Pathway Analysis (IPA). In the expression analysis, necroptosis and sirtuin signalling pathways, mitochondrial dysfunction, and inflammasome were the top canonical pathways for both TSPOAP1 and TSPO, confirming the close relationship between these two proteins. A distribution analysis of common proteins in all the canonical pathways predicted for TSPOAP1 revealed that tumor necrosis factor receptor 1 (TNFR1), vascular cell adhesion molecule 1 (VCAM1), cyclic AMP response element-binding protein 1 (CREB1), T-cell receptor (TCR), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3), DNA-dependent protein kinase (DNA-PK or PRKDC), and mitochondrial permeability transition pore (mPTP) were the major interaction partners of TSPOAP1, highlighting the role of TSPOAP1 in inflammation, particularly neuroinflammation. An analysis of the overlap between TSPO and TSPOAP1 Homo sapiens genes and top-ranked canonical pathways indicated that TSPO and TSPOAP1 interact via voltage-dependent anion-selective channels (VDAC1/2/3). A heat map analysis indicated that TSPOAP1 has critical roles in inflammatory, neuroinflammatory, psychiatric, and metabolic diseases and disorders, and cancer. Taken together, this information improves our understanding of the mechanism of action and biological functions of TSPOAP1 as well as its relationship with TSPO; furthermore, these results could provide new directions for in-depth functional studies of TSPOAP1 aimed at unmasking its detailed functions.

Region-based analysis with functional annotation identifies genes associated with cognitive function in South Asians from India

“…Translocator protein (TSPO) associated protein 1 ( TSPOAP1 ) regulates calcium channels in nerve synapses [50]. It interacts with the protein TSPO which is involved in inflammation pathways [51]. TSPOAP1 variants were associated with AD in a large transethnic AD GWAS [52].…”

Analysis of differentially expressed genes in torn rotator cuff tendon tissues in diabetic patients through RNA-sequencing

“…TSPOAP1 was strongly linked with HAGLR-207 and was also the most-linked mRNA in ceRNA network. In fact, it mediates the inflammatory feedback through TNFR1 and downstream NF-κB, a transcription factor that promotes inflammation [ 49 ] and has been reported to involve in tendinopathic and ruptured Achilles tendon [ 50 ]. Furthermore, it plays a central role in inflammation by modulating the response of NLRP3 inflammasome, which is induced by TLR ligands, such as lipopolysaccharide via NF-κB signaling [ 49 ].…”

“…In fact, it mediates the inflammatory feedback through TNFR1 and downstream NF-κB, a transcription factor that promotes inflammation [ 49 ] and has been reported to involve in tendinopathic and ruptured Achilles tendon [ 50 ]. Furthermore, it plays a central role in inflammation by modulating the response of NLRP3 inflammasome, which is induced by TLR ligands, such as lipopolysaccharide via NF-κB signaling [ 49 ]. Since it was upregulated in diabetic RCT patients, investigating the role of TSPOAP1 mediated inflammation could provide new directions for in-depth studies of DM affecting RCT.…”

Ingenuity pathway analysis of α-synuclein predicts potential signaling pathways, network molecules, biological functions, and its role in neurological diseases

“…To observe the effect of possible mutations in IPA predictions, all types of mutations and effects, such as functional effect, inheritance mode, translation impact, unclassified mutations, zygosity, and wild type, were selected. The results were ranked based on Fisher’s exact test, where the smaller P -value indicates the higher significance of predicted results ( IPA, 2021 ; Suthar et al, 2021 ). GraphPad Prism 6 was used to plot the graphs at various stages of the study.…”

“…IPA was performed by selecting the following options/parameters step-by-step available for selection on the IPA server ( IPA, 2021 ); (i) the NCBI text file of the respective gene was imported onto the QIAGEN IPA server for a new core analysis, (ii) the imported text file was retained in the flexible format and the gene identification (GI) number of the SNCA/APP/MAPT/HTT was defined, (iii) IPA function “toxicity analysis” was chosen for the study, (iv) for the population of genes to be considered for P -value calculations, the reference set was limited to the Ingenuity Knowledge Base genes only, (v) for SNCA/APP/MAPT/HTT molecular network generation, we opted for molecules displaying both direct and indirect relationships in the network, (vi) furthermore, for SNCA/APP/MAPT/HTT molecular network generation, we opted for molecules exhibiting interaction networks as well as casual networks, (vii) an interaction network contained 35 molecules per network and 25 networks per analysis, (viii) the types of molecules to be included for network generation (referred to as node types), all node types, such as biological drugs, chemicals, complexes, cytokines, diseases, enzymes, etc. were selected, (ix) to consider the data sources for IPA predictions, all the data sources available on the IPA server were chosen, (x) to predict the relationships among the network molecules, the data sources with only experimentally observed molecular relationships were considered, (xi) IPA predictions were kept limited to the human species only, (xii) to opt for the data source experiments performed in the types of the organ system, tissues, and cell lines for IPA predictions, analysis was kept limited to the experimental results from tissues, cells, nervous system, and organ system only, (xiii) to consider the mutated molecules appearing in the network generation, all types of mutations, such as functional, inherited, translational, zygotic, and unclassified, were chosen, and (xiv) IPA prediction results were ranked based on the significance value ( P -value) calculated by the right-tailed Fisher’s exact test ( Suthar et al, 2021 ).…”