Generic placeholder image

Current Molecular Pharmacology


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

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



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.

Gut, P.; Verdin, E. The nexus of chromatin regulation and intermediary metabolism. Nature, 2013, 502(7472), 489-498.
[] [PMID: 24153302]
Thomas, P.D.; Kahn, M. Kat3 coactivators in somatic stem cells and cancer stem cells: Biological roles, evolution, and pharmacologic manipulation. Cell Biol. Toxicol., 2016, 32(1), 61-81.
[] [PMID: 27008332]
Bricambert, J.; Miranda, J.; Benhamed, F.; Girard, J.; Postic, C.; Dentin, R. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J. Clin. Invest., 2010, 120(12), 4316-4331.
[] [PMID: 21084751]
Liu, Y.; Dentin, R.; Chen, D.; Hedrick, S.; Ravnskjaer, K.; Schenk, S.; Milne, J.; Meyers, D.J.; Cole, P.; Iii, J.Y.; Olefsky, J.; Guarente, L.; Montminy, M. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature, 2008, 456(7219), 269-273.
[] [PMID: 18849969]
Rieger, M.E.; Zhou, B.; Solomon, N.; Sunohara, M.; Li, C.; Nguyen, C.; Liu, Y.; Pan, J.; Minoo, P.; Crandall, E.D.; Brody, S.L.; Kahn, M.; Borok, Z. p300/β-catenin interactions regulate adult progenitor cell differentiation downstream of WNT5a/Protein Kinase C (PKC). J. Biol. Chem., 2016, 291(12), 6569-6582.
[] [PMID: 26833564]
Lai, K.K.Y.; Hu, X.; Chosa, K.; Nguyen, C.; Lin, D.P.; Lai, K.K.; Kato, N.; Higuchi, Y.; Highlander, S.K.; Melendez, E.; Eriguchi, Y.; Fueger, P.T.; Ouellette, A.J.; Chimge, N.O.; Ono, M.; Kahn, M. p300 Serine 89: A critical signaling integrator and its effects on intestinal homeostasis and repair. Cancers, 2021, 13(6), 1288.
[] [PMID: 33799418]
Grossman, L.I.; Schmidt, T.R.; Wildman, D.E.; Goodman, M. Molecular evolution of aerobic energy metabolism in primates. Mol. Phylogenet. Evol., 2001, 18(1), 26-36.
[] [PMID: 11161739]
Cáceres, M.; Lachuer, J.; Zapala, M.A.; Redmond, J.C.; Kudo, L.; Geschwind, D.H.; Lockhart, D.J.; Preuss, T.M.; Barlow, C. Elevated gene expression levels distinguish human from non-human primate brains. Proc. Natl. Acad. Sci., 2003, 100(22), 13030-13035.
[] [PMID: 14557539]
Uddin, M.; Wildman, D.E.; Liu, G.; Xu, W.; Johnson, R.M.; Hof, P.R.; Kapatos, G.; Grossman, L.I.; Goodman, M. Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles. Proc. Natl. Acad. Sci., 2004, 101(9), 2957-2962.
[] [PMID: 14976249]
Haygood, R.; Fedrigo, O.; Hanson, B.; Yokoyama, K.D.; Wray, G.A. Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution. Nat. Genet., 2007, 39(9), 1140-1144.
[] [PMID: 17694055]
Pontzer, H.; Brown, M.H.; Raichlen, D.A.; Dunsworth, H.; Hare, B.; Walker, K.; Luke, A.; Dugas, L.R.; Durazo-Arvizu, R.; Schoeller, D.; Plange-Rhule, J.; Bovet, P.; Forrester, T.E.; Lambert, E.V.; Thompson, M.E.; Shumaker, R.W.; Ross, S.R. Metabolic acceleration and the evolution of human brain size and life history. Nature, 2016, 533(7603), 390-392.
[] [PMID: 27144364]
Hoyer, S. The young-adult and normally aged brain. Its blood flow and oxidative metabolism. A review - part I. Arch. Gerontol. Geriatr., 1982, 1(2), 101-116.
[] [PMID: 6821143]
Hoyer, S. The abnormally aged brain. Its blood flow and oxidative metabolism. A review - Part II. Arch. Gerontol. Geriatr., 1982, 1(3), 195-207.
[] [PMID: 6764604]
Luttik, K.; Tejwani, L.; Ju, H.; Driessen, T.; Smeets, C.J.L.M.; Edamakanti, C.R.; Khan, A.; Yun, J.; Opal, P.; Lim, J. Differential effects of Wnt-β-catenin signaling in Purkinje cells and Bergmann glia in spinocerebellar ataxia type 1. Proc. Natl. Acad. Sci., 2022, 119(34), e2208513119.
[] [PMID: 35969780]
Hu, X.; Ono, M.; Chimge, N.O.; Chosa, K.; Nguyen, C.; Melendez, E.; Lou, C.H.; Lim, P.; Termini, J.; Lai, K.K.Y.; Fueger, P.T.; Teo, J.L.; Higuchi, Y.; Kahn, M. Differential Kat3 usage orchestrates the integration of cellular metabolism with differentiation. Cancers, 2021, 13(23), 5884.
[] [PMID: 34884992]
Teo, J.L.; Ma, H.; Nguyen, C.; Lam, C.; Kahn, M. Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Proc. Natl. Acad. Sci., 2005, 102(34), 12171-12176.
[] [PMID: 16093313]
Ono, M.; Lai, K.K.Y.; Wu, K.; Nguyen, C.; Lin, D.P.; Murali, R.; Kahn, M. Nuclear receptor/Wnt beta-catenin interactions are regulated via differential CBP/p300 coactivator usage. PLoS One, 2018, 13(7), e0200714.
[] [PMID: 30020971]
Pietrocola, F.; Galluzzi, L.; Bravo-San Pedro, J.M.; Madeo, F.; Kroemer, G. Acetyl coenzyme A: A central metabolite and second messenger. Cell Metab., 2015, 21(6), 805-821.
[] [PMID: 26039447]
Mews, P.; Donahue, G.; Drake, A.M.; Luczak, V.; Abel, T.; Berger, S.L. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature, 2017, 546(7658), 381-386.
[] [PMID: 28562591]
McBurney, M.W.; Jones-Villeneuve, E.M.V.; Edwards, M.K.S.; Anderson, P.J. Control of muscle and neuronal differentiation in a cultured embryonal carcinoma cell line. Nature, 1982, 299(5879), 165-167.
[] [PMID: 7110336]
Harada, N.; Nishiyama, S.; Kanazawa, M.; Tsukada, H. Development of novel PET probes, [18F]BCPP-EF, [18F]BCPP-BF, and [11C]BCPP-EM for mitochondrial complex 1 imaging in the living brain. J. Labelled Comp. Radiopharm., 2013, 56(11), 553-561.
[] [PMID: 24285187]
Kahn, M. Taking the road less traveled – the therapeutic potential of CBP/β-catenin antagonists. Expert Opin. Ther. Targets, 2021, 25(9), 701-719.
[] [PMID: 34633266]
Yuan, L.W.; Gambee, J.E. Phosphorylation of p300 at serine 89 by protein kinase C. J. Biol. Chem., 2000, 275(52), 40946-40951.
[] [PMID: 11020388]
Egervari, G.; Glastad, K.M.; Berger, S.L. Food for thought. Science, 2020, 370(6517), 660-662.
[] [PMID: 33154125]
Bradshaw, P.C. Acetyl-CoA metabolism and histone acetylation in the regulation of aging and lifespan. Antioxidants, 2021, 10(4), 572.
[] [PMID: 33917812]
Mishra, R.; Phan, T.; Kumar, P.; Morrissey, Z.; Gupta, M.; Hollands, C.; Shetti, A.; Lopez, K.L.; Maienschein-Cline, M.; Suh, H.; Hen, R.; Lazarov, O. Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease by restoring the memory-storing neurons. J. Exp. Med., 2022, 219(9), e20220391.
[] [PMID: 35984475]
Zhou, Y.; Su, Y.; Li, S.; Kennedy, B.C.; Zhang, D.Y.; Bond, A.M.; Sun, Y.; Jacob, F.; Lu, L.; Hu, P.; Viaene, A.N.; Helbig, I.; Kessler, S.K.; Lucas, T.; Salinas, R.D.; Gu, X.; Chen, H.I.; Wu, H.; Kleinman, J.E.; Hyde, T.M.; Nauen, D.W.; Weinberger, D.R.; Ming, G.; Song, H. Molecular landscapes of human hippocampal immature neurons across lifespan. Nature, 2022, 607(7919), 527-533.
[] [PMID: 35794479]
Li, X.; Yu, W.; Qian, X.; Xia, Y.; Zheng, Y.; Lee, J.H.; Li, W.; Lyu, J.; Rao, G.; Zhang, X.; Qian, C.N.; Rozen, S.G.; Jiang, T.; Lu, Z. Nucleus-translocated acss2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol. Cell, 2017, 66(5), 684-697.e9.
[] [PMID: 28552616]
Barnett, A.; Brewer, G.J. Autophagy in aging and Alzheimer’s disease: Pathologic or protective? J. Alzheimers Dis., 2011, 25(3), 385-394.
[] [PMID: 21422527]
Settembre, C.; De Cegli, R.; Mansueto, G.; Saha, P.K.; Vetrini, F.; Visvikis, O.; Huynh, T.; Carissimo, A.; Palmer, D.; Jürgen Klisch, T.; Wollenberg, A.C.; Di Bernardo, D.; Chan, L.; Irazoqui, J.E.; Ballabio, A. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol., 2013, 15(6), 647-658.
[] [PMID: 23604321]
Qin, W.; Haroutunian, V.; Katsel, P.; Cardozo, C.P.; Ho, L.; Buxbaum, J.D.; Pasinetti, G.M. PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch. Neurol., 2009, 66(3), 352-361.
[] [PMID: 19273754]
Handschin, C.; Kobayashi, Y.M.; Chin, S.; Seale, P.; Campbell, K.P.; Spiegelman, B.M. PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev., 2007, 21(7), 770-783.
[] [PMID: 17403779]
Lesnefsky, E.J.; Hoppel, C.L. Oxidative phosphorylation and aging. Ageing Res. Rev., 2006, 5(4), 402-433.
[] [PMID: 16831573]
Sebastián, D.; Palacín, M.; Zorzano, A. Mitochondrial dynamics: Coupling mitochondrial fitness with healthy aging. Trends Mol. Med., 2017, 23(3), 201-215.
[] [PMID: 28188102]
Tavallaie, M.; Voshtani, R.; Deng, X.; Qiao, Y.; Jiang, F.; Collman, J.P.; Fu, L. Moderation of mitochondrial respiration mitigates metabolic syndrome of aging. Proc. Natl. Acad. Sci., 2020, 117(18), 9840-9850.
[] [PMID: 32303655]
Sharpless, N.E.; DePinho, R.A. How stem cells age and why this makes us grow old. Nat. Rev. Mol. Cell Biol., 2007, 8(9), 703-713.
[] [PMID: 17717515]
MacNee, W.; Rabinovich, R.A.; Choudhury, G. Ageing and the border between health and disease. Eur. Respir. J., 2014, 44(5), 1332-1352.
[] [PMID: 25323246]
Goodman, A.B.; Pardee, A.B. Evidence for defective retinoid transport and function in late onset Alzheimer’s disease. Proc. Natl. Acad. Sci., 2003, 100(5), 2901-2905.
[] [PMID: 12604774]
Pedrero-Prieto, C.M.; Frontiñán-Rubio, J.; Alcaín, F.J.; Durán-Prado, M.; Peinado, J.R.; Rabanal-Ruiz, Y. Biological significance of the protein changes occurring in the cerebrospinal fluid of alzheimer’s disease patients: Getting clues from proteomic studies. Diagnostics, 2021, 11(9), 1655.
[] [PMID: 34573996]
Lukaszewicz, A.I.; Nguyen, C.; Melendez, E.; Lin, D.P.; Teo, J.L.; Lai, K.K.Y.; Huttner, W.B.; Shi, S.H.; Kahn, M. The mode of stem cell division is dependent on the differential interaction of β-catenin with the Kat3 coactivators CBP or p300. Cancers, 2019, 11(7), 962.
[] [PMID: 31324005]

© 2024 Bentham Science Publishers | Privacy Policy