PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer's Disease: A Data Mining and Bioinformatics Study.
PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer's Disease: A Data Mining and Bioinformatics Study.
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DOI：
10.3390/ijms23094568
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发表时间：
2022-04-20
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
β位点淀粉样蛋白前体蛋白切割酶1 （BACE1）是阿尔茨海默病（AD）的一个广泛研究的治疗靶点，因为它在神经毒性淀粉样蛋白（Aβ）肽的产生中起作用。然而，尽管大量BACE1抑制剂进入临床试验，但没有一种抑制剂能有效降低Aβ浓度，从而成功改善AD的发病机制。这在一定程度上可归因于对BACE1的不完全了解，包括其生理功能和底物特异性。我们认为BACE1具有其他重要的生理功能，其介导的底物仍有待鉴定。因此，为了解决这个问题，我们计算分析了从文献中鉴定出的533种BACE1依赖性蛋白，以寻找潜在的BACE1底物，并将它们与AD中差异表达的蛋白进行比较。我们发现了15个新的BACE1底物在AD中被特异性改变。为了证实我们的分析，我们使用Western blotting验证了蛋白酪氨酸磷酸酶受体D型（PTPRD）和Netrin受体DCC （DCC）。这些发现揭示了BACE1抑制剂的缺陷，并可以设计针对替代BACE1底物的底物特异性抑制剂。此外，它使我们对BACE1在AD中的作用及其功能障碍有了更深入的了解。
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.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
5
作者：
Honorato RV;Koukos PI;Jiménez-García B;Tsaregorodtsev A;Verlato M;Giachetti A;Rosato A;Bonvin AMJJ
通讯作者：
Bonvin AMJJ
影响因子：
4.8
作者：
Hitt, Brian;Riordan, Sean M.;Vassar, Robert
通讯作者：
Vassar, Robert
影响因子：
11
作者：
Chiba, T.;Yamada, M.;Aiso, S.
通讯作者：
Aiso, S.
脑淀粉样血管病对内皮的影响。
影响因子：
3.9
作者：
Grinberg, Lea Tenenholz;Korczyn, Amos D.;Heinsen, Helmut
通讯作者：
Heinsen, Helmut