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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Differential Kat3 Coactivator Usage Regulates Brain Metabolism and Neuronal Differentiation

Author(s): Erasmus Kofi Poku, Masaya Ono, Yusuke Higuchi, Junie Chea, Elizabeth Melendez, Jia-Ling Teo, Cu Nguyen, Nyam-Osor Chimge and Michael Kahn*

Volume 17, 2024

Published on: 28 August, 2023

Article ID: e170823219875 Pages: 9

DOI: 10.2174/1874467217666230817092415

open_access

Abstract

Introduction: Our previous work has demonstrated significant effects on the oxidative stress response, mitochondrial function, and oxidative phosphorylation in the livers and intestines of p300 S89A knockin (S89AKI) mice. We now show that this mutation is also associated with brain metabolic defects and neuronal differentiation.

Methods: p300 S89A edited P19 cells, and S89AKI mice demonstrated metabolic and neuronal differentiation defects based on proteomic, cell biological and PET imaging studies.

Results: The metabolic and differentiation defects associated with the p300 S89A knockin mutation could be corrected both in vitro and in vivo utilizing the small molecule CBP/beta-catenin antagonist ICG-001.

Conclusion: Rebalancing the equilibrium between CBP/β-catenin versus p300/β-catenin associated transcription, utilizing the small molecule CBP/beta-catenin antagonist ICG-001, enhances mitochondrial oxidative phosphorylation, metabolic function, and neuronal differentiation and may be able to ameliorate the cognitive decline seen in neurodegenerative disorders, including Alzheimer’s Disease.

Keywords: CBP, p300, ICG-001, Metabolism, Neurodegeneration, Kat3.

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