Publication: Melatonin prevents neddylation dysfunction in aβ42-exposed sh-sy5y neuroblastoma cells by regulating the amyloid precursor protein-binding protein 1 pathway
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Issued Date
2020-01-01
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ISSN
18755828
15672050
15672050
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2-s2.0-85089679963
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Mahidol University
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SCOPUS
Bibliographic Citation
Current Alzheimer Research. Vol.17, No.5 (2020), 446-459
Suggested Citation
Mayuri Shukla, Vorapin Chinchalongporn, Piyarat Govitrapong Melatonin prevents neddylation dysfunction in aβ42-exposed sh-sy5y neuroblastoma cells by regulating the amyloid precursor protein-binding protein 1 pathway. Current Alzheimer Research. Vol.17, No.5 (2020), 446-459. doi:10.2174/1567205017666200624201356 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/59275
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Title
Melatonin prevents neddylation dysfunction in aβ42-exposed sh-sy5y neuroblastoma cells by regulating the amyloid precursor protein-binding protein 1 pathway
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Abstract
© 2020 Bentham Science Publishers. Background: Amyloid Precursor Protein (APP)-Binding Protein 1 (APP-BP1) is a crucial regulator of many key signaling pathways and functions mainly as a scaffold protein to enhance molecular interactions and facilitate catalytic reactions. The interaction of APP-BP1 with Amyloid Precursor Protein (APP) plays a role in cell cycle transit control, which determines the mechanism behind the loss of cell cycle regulation in Alzheimer’s Disease (AD). In contrast, neddylation, a posttranslational modification mediated by conjugation of ubiquitin-like protein neural precursor cell expressed developmen-tally downregulated protein 8 (NEDD8), is activated by a heterodimer composed of APP-BP1 and NEDD8-activating enzyme E1 catalytic subunit (Uba3). NEDD8 controls vital biological events, and along with APP-BP1, its levels are deregulated in AD. Objective: The present study investigated the role of melatonin in regulating the APP-BP1 pathway under both physiological and pathological conditions to develop an understanding of the underlying mechanisms. Methods: Therefore, human SH-SY5Y neuroblastoma cells were treated with various concentrations of Aβ42 to induce neurotoxic conditions comparable to AD. Results: The results are the first to demonstrate that melatonin prevents Aβ42-induced enhancement of APP-BP1 protein expression and alteration in the cellular localization of NEDD8. Moreover, using MLN4924 (APP-BP1 pathway blocker), we also verified the components of the downstream effector cascade of the APP-BP1 pathway, including tau, APP-cleaving secretases, β-catenin and p53. Conclusion: These findings indicate that melatonin regulates the interplay of molecular signaling associated with the APP-BP1 pathway and might preclude the pathogenic mechanisms occurring during disease development, thus providing a propitious therapeutic strategy for preventing AD.