Differential Kat3 Coactivator Usage Regulates Brain Metabolism and Neuronal Differentiation.

Area of Science:

• Biochemistry
• Neuroscience
• Cell Biology

Background:

• Previous studies linked the p300 S89A knockin (S89AKI) mutation to impaired oxidative stress response and mitochondrial function in mouse livers and intestines.
• This study investigates the impact of the S89AKI mutation on brain metabolism and neuronal differentiation.

Purpose of the Study:

• To investigate the effects of the p300 S89A mutation on brain metabolic function and neuronal differentiation.
• To evaluate the therapeutic potential of the CBP/beta-catenin antagonist ICG-001 in correcting these defects.

Main Methods:

• Utilized p300 S89A edited P19 cells and S89AKI mice.
• Employed proteomic, cell biological, and PET imaging studies to assess metabolic and differentiation phenotypes.
• Investigated the efficacy of ICG-001 in vitro and in vivo.

Main Results:

• The p300 S89A mutation was associated with significant brain metabolic defects and impaired neuronal differentiation.
• These defects were successfully corrected both in vitro and in vivo by the small molecule ICG-001.
• ICG-001 demonstrated the ability to rebalance CBP/β-catenin and p300/β-catenin transcriptional activity.

Conclusions:

• The CBP/beta-catenin antagonist ICG-001 enhances mitochondrial oxidative phosphorylation, metabolic function, and neuronal differentiation.
• Rebalancing transcription via ICG-001 offers a potential therapeutic strategy for cognitive decline in neurodegenerative disorders, including Alzheimer's Disease.