Title:Differential Kat3 Coactivator Usage Regulates Brain Metabolism and Neuronal
Differentiation
Volume: 17
Author(s): Erasmus Kofi Poku, Masaya Ono, Yusuke Higuchi, Junie Chea, Elizabeth Melendez, Jia-Ling Teo, Cu Nguyen, Nyam-Osor Chimge and Michael Kahn*
Affiliation:
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
Keywords:
CBP, p300, ICG-001, Metabolism, Neurodegeneration, Kat3.
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.
