PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study
The β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is an extensively studied therapeutic target for Alzheimer’s disease (AD), owing to its role in the production of neurotoxic amyloid beta (Aβ) peptides. However, despite numerous BACE1 inhibitors entering clinical trials, none have succe...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/9/4568 |
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| author | Hannah A. Taylor Katie J. Simmons Eva M. Clavane Christopher J. Trevelyan Jane M. Brown Lena Przemyłska Nicole T. Watt Laura C. Matthews Paul J. Meakin |
| author_facet | Hannah A. Taylor Katie J. Simmons Eva M. Clavane Christopher J. Trevelyan Jane M. Brown Lena Przemyłska Nicole T. Watt Laura C. Matthews Paul J. Meakin |
| author_sort | Hannah A. Taylor |
| collection | DOAJ |
| description | The β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is an extensively studied therapeutic target for Alzheimer’s disease (AD), owing to its role in the production of neurotoxic amyloid beta (Aβ) peptides. However, despite numerous BACE1 inhibitors entering clinical trials, none have successfully improved AD pathogenesis, despite effectively lowering Aβ concentrations. This can, in part, be attributed to an incomplete understanding of BACE1, including its physiological functions and substrate specificity. We propose that BACE1 has additional important physiological functions, mediated through substrates still to be identified. Thus, to address this, we computationally analysed a list of 533 BACE1 dependent proteins, identified from the literature, for potential BACE1 substrates, and compared them against proteins differentially expressed in AD. We identified 15 novel BACE1 substrates that were specifically altered in AD. To confirm our analysis, we validated Protein tyrosine phosphatase receptor type D (PTPRD) and Netrin receptor DCC (DCC) using Western blotting. These findings shed light on the BACE1 inhibitor failings and could enable the design of substrate-specific inhibitors to target alternative BACE1 substrates. Furthermore, it gives us a greater understanding of the roles of BACE1 and its dysfunction in AD. |
| first_indexed | 2024-03-10T04:07:30Z |
| format | Article |
| id | doaj.art-ae277e114f73481a997d54c004390222 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:07:30Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ae277e114f73481a997d54c0043902222023-11-23T08:19:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01239456810.3390/ijms23094568PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics StudyHannah A. Taylor0Katie J. Simmons1Eva M. Clavane2Christopher J. Trevelyan3Jane M. Brown4Lena Przemyłska5Nicole T. Watt6Laura C. Matthews7Paul J. Meakin8Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKLeeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UKThe β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is an extensively studied therapeutic target for Alzheimer’s disease (AD), owing to its role in the production of neurotoxic amyloid beta (Aβ) peptides. However, despite numerous BACE1 inhibitors entering clinical trials, none have successfully improved AD pathogenesis, despite effectively lowering Aβ concentrations. This can, in part, be attributed to an incomplete understanding of BACE1, including its physiological functions and substrate specificity. We propose that BACE1 has additional important physiological functions, mediated through substrates still to be identified. Thus, to address this, we computationally analysed a list of 533 BACE1 dependent proteins, identified from the literature, for potential BACE1 substrates, and compared them against proteins differentially expressed in AD. We identified 15 novel BACE1 substrates that were specifically altered in AD. To confirm our analysis, we validated Protein tyrosine phosphatase receptor type D (PTPRD) and Netrin receptor DCC (DCC) using Western blotting. These findings shed light on the BACE1 inhibitor failings and could enable the design of substrate-specific inhibitors to target alternative BACE1 substrates. Furthermore, it gives us a greater understanding of the roles of BACE1 and its dysfunction in AD.https://www.mdpi.com/1422-0067/23/9/4568Alzheimer’s diseasebeta secretase 1 (BACE1)Netrin receptor DCCprotein tyrosine phosphatase receptor type D (PTPRD)BACE1 substrates |
| spellingShingle | Hannah A. Taylor Katie J. Simmons Eva M. Clavane Christopher J. Trevelyan Jane M. Brown Lena Przemyłska Nicole T. Watt Laura C. Matthews Paul J. Meakin PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study International Journal of Molecular Sciences Alzheimer’s disease beta secretase 1 (BACE1) Netrin receptor DCC protein tyrosine phosphatase receptor type D (PTPRD) BACE1 substrates |
| title | PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study |
| title_full | PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study |
| title_fullStr | PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study |
| title_full_unstemmed | PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study |
| title_short | PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study |
| title_sort | ptprd and dcc are novel bace1 substrates differentially expressed in alzheimer s disease a data mining and bioinformatics study |
| topic | Alzheimer’s disease beta secretase 1 (BACE1) Netrin receptor DCC protein tyrosine phosphatase receptor type D (PTPRD) BACE1 substrates |
| url | https://www.mdpi.com/1422-0067/23/9/4568 |
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