差异型 Kat3 共激活因子的作用调节脑代谢和神经元分化。
Differential Kat3 Coactivator Usage Regulates Brain Metabolism and Neuronal Differentiation.
机构信息
Department of Radiopharmacy, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
出版信息
Curr Mol Pharmacol. 2024;17(1):e170823219875. doi: 10.2174/1874467217666230817092415.
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.
简介
我们之前的工作已经证明了 p300 S89A 点突变（S89AKI）对肝脏和肠道的氧化应激反应、线粒体功能和氧化磷酸化有显著影响。现在我们发现该突变也与大脑代谢缺陷和神经元分化有关。
方法
p300 S89A 编辑的 P19 细胞，以及 S89AKI 小鼠，通过蛋白质组学、细胞生物学和正电子发射断层扫描成像研究显示出代谢和神经元分化缺陷。
结果
利用小分子 CBP/β-连环蛋白拮抗剂 ICG-001，在体外和体内都可以纠正与 p300 S89A 点突变相关的代谢和分化缺陷。
结论
利用小分子 CBP/β-连环蛋白拮抗剂 ICG-001 重新平衡 CBP/β-连环蛋白与 p300/β-连环蛋白相关转录之间的平衡，增强线粒体氧化磷酸化、代谢功能和神经元分化，可能能够改善神经退行性疾病（包括阿尔茨海默病）中观察到的认知能力下降。
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