Melatonin Prevents Neddylation Dysfunction in Aβ42-Exposed SH-SY5Y Neuroblastoma Cells by Regulating the Amyloid Precursor Protein- Binding Protein 1 Pathway.

Abstract

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 developmentally 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.

• Authors: Mayuri Shukla, Vorapin Chinchalongporn, Piyarat Govitrapong
• Journal: Current Alzheimer research (Curr Alzheimer Res) Vol. 17 Issue 5 Pg. 446-459 ( 2020) ISSN: 1875-5828 [Electronic] United Arab Emirates
• PMID: 32579500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Amyloid beta-Peptides
• Antioxidants
• NEDD8 Protein
• NEDD8 protein, human
• Peptide Fragments
• amyloid beta-protein (1-42)
• Ubiquitin-Activating Enzymes
• NAE protein, human
• Melatonin

Topics

• Amyloid beta-Peptides (toxicity)
• Antioxidants (pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Humans
• Melatonin (pharmacology)
• NEDD8 Protein (metabolism)
• Neuroblastoma (metabolism)
• Peptide Fragments (toxicity)
• Signal Transduction (drug effects, physiology)
• Ubiquitin-Activating Enzymes (antagonists & inhibitors, biosynthesis)