Abstract
Recently, all applications of BACE1 inhibitors failed as therapeutical targets for Alzheimer´s disease (AD) due to severe side effects. Therefore, alternative ways for treatment development are a hot research topic. The present analysis investigates BACE1 protein–protein interaction networks and attempts to solve the absence of complete knowledge about pathways involving BACE1. A bioinformatics analysis matched the functions of the non-substrate interaction network with Voltage-gated potassium channels, which also appear as top priority protein nodes. Targeting BACE1 interactions with PS1 and GGA-s, blocking of BACE1 access to APP by BRI3 and RTN-s, activation of Wnt signaling and upregulation of β-catenin, and brain delivery of the extracellular domain of p75NTR, are the main alternatives to the use of BACE 1 inhibitors highlighted by the analysis. The pathway enrichment analysis also emphasized substrates and substrate candidates with essential biological functions, which cleavage must remain controlled. They include ephrin receptors, ROBO1, ROBO2, CNTN-s, CASPR-s, CD147, CypB, TTR, APLP1/APLP2, NRXN-s, and PTPR-s. The analysis of the interaction subnetwork of BACE1 functionally related to inflammation identified a connection to three cardiomyopathies, which supports the hypothesis of the common molecular mechanisms with AD. A lot of potential shows the regulation of BACE1 activity through post-translational modifications. The interaction network of BACE1 and its phosphorylation enzyme CSNK1D functionally match the Circadian clock, p53, and Hedgehog signaling pathways. The regulation of BACE1 glycosylation could be achieved through N-acetylglucosamine transferases, α-(1→6)-fucosyltransferase, β-galactoside α-(2→6)-sialyltransferases, galactosyltransferases, and mannosidases suggested by the interaction network analysis of BACE1-MGAT3. The present analysis proposes possibilities for the alternative control of AD pathology.
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All data generated or analyzed during this study are included in this published article and its supplementary information files Table S1–S3.
Abbreviations
- BBB:
-
Blood–brain barrier
- CAM:
-
Cell adhesion molecule
- DRM:
-
Detergent-resistant membrane
- ER:
-
Endoplasmic reticulum
- ECM:
-
Extracellular matrix organization
- FN:
-
Fibronectin
- GB:
-
Glioblastoma
- GGA:
-
Golgi associated
- GPI:
-
Glycosylphosphatidylinositol
- GGA:
-
Golgi associated, gamma-adaptin ear-containing, ARF-binding protein
- HA:
-
Hyaluronan
- IGF:
-
Insulin-like growth factor
- IGFBP:
-
Insulin-like growth factor-binding protein
- KO:
-
Knockout
- L1CAM:
-
L1 cell adhesion molecule protein
- PTP:
-
Protein-tyrosine phosphatase
- PTPR:
-
Protein-tyrosine phosphatase, receptor-type
- PPIN:
-
Protein–protein interaction network
- RTN:
-
Reticulon
- MMP:
-
Matrix metalloproteinase
- NRX:
-
Neurexin
- TGN:
-
Trans-golgi network
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The research was conducted from the financial resources of Biochemworld co., Uppsala County, Sweden.
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232_2022_225_MOESM1_ESM.xlsx
Supplementary file1 (XLSX 70 KB) The full result of the pathway enrichment and gene function prediction analysis of the BACE1 non-substrate PPIN. The network was constructed by GeneMania (3.5.2) application run under Cytoscape (3.9.0) environment utilizing the H. sapiens database (update 13-07-2017) and including all types of interaction networks. The table also includes the input protein list (column Gene 7-35)
232_2022_225_MOESM2_ESM.xlsx
Supplementary file2 (XLSX 373 KB) The full result of the pathway enrichment and gene function analysis of the BACE1 substrate PPIN. The network was constructed by applying the GeneMania (3.5.2) application run under Cytoscape (3.7.2) environment utilizing the H. sapiens database (update 13-07-2017) and including all types of interaction networks. The table also includes the input protein list (column Gene 7-226)
232_2022_225_MOESM3_ESM.xlsx
Supplementary file3 (XLSX 67 KB) The full result of the pathway enrichment analysis and gene function prediction analysis of the interaction network of BACE1 and its substrates PRTG, VCAM1, ST6GAL1, and the integrins glycosylated by ST6GAL1 (ITGA5, ITGA4, ITGB1). The network was constructed by applying the GeneMania (3.5.2) application run under Cytoscape (3.7.2) environment utilizing the H. sapiens database (update 13-07-2017) and including all types of the interaction networks
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Nahálková, J. Finding New Ways How to Control BACE1. J Membrane Biol 255, 293–318 (2022). https://doi.org/10.1007/s00232-022-00225-1
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DOI: https://doi.org/10.1007/s00232-022-00225-1