Simvastatin Restores HDAC1/2 Activity and Improves Behavioral Deficits in Angelman Syndrome Model Mouse

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2019 Dec 19

PMID 31849603

Citations 8

Authors

Vipendra Kumar

Tripti Joshi

Naman Vatsa

Brijesh Kumar Singh

Nihar Ranjan Jana

Affiliations

Soon will be listed here.

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder categorized by severe disability in intellectual functions and affected by the loss of function of maternally inherited gene. Mice deficient for the maternal recapitulates many distinguishing behavioral features of the AS and is used as a typical model system to understand the disease pathogenic mechanism. Here, we first show a significant increase in HDAC1 and HDAC2 activities in AS mice brain from as early as embryonic day 16(E16). In depth study further reveals that the deficiency of Ube3a leads to transcriptional up-regulation of both HDAC1 and HDAC2. Restoration of HDAC1 and HDAC2 activities (as evident from the increased acetylation of histones H3 and H4) using simvastatin significantly improves the cognitive deficit and social interaction behavior in AS mice. Simvastatin treatment also restores the reduced level of BDNF in AS mice brain. Finally, we demonstrate that the treatment of simvastatin to primary cortical neuronal culture prepared from AS mice embryo also rescues altered acetylation of histones H3 and H4 and the level of BDNF. These results suggest that simvastatin could be a promising drug for the treatment of AS.

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References

Silva-Santos S, van Woerden G, Bruinsma C, Mientjes E, Aghadavoud Jolfaei M, Distel B . Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. J Clin Invest. 2015; 125(5):2069-76. PMC: 4463212. DOI: 10.1172/JCI80554. View

Sun J, Zhu G, Liu Y, Standley S, Ji A, Tunuguntla R . UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis. Cell Rep. 2015; 12(3):449-61. PMC: 4520703. DOI: 10.1016/j.celrep.2015.06.023. View

Li G, Larson E, Sonnen J, Shofer J, Petrie E, Schantz A . Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology. 2007; 69(9):878-85. DOI: 10.1212/01.wnl.0000277657.95487.1c. View

Graff J, Kim D, Dobbin M, Tsai L . Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol Rev. 2011; 91(2):603-49. DOI: 10.1152/physrev.00012.2010. View

Williams C, Driscoll D, Dagli A . Clinical and genetic aspects of Angelman syndrome. Genet Med. 2010; 12(7):385-95. DOI: 10.1097/GIM.0b013e3181def138. View

Yamakawa H, Cheng J, Penney J, Gao F, Rueda R, Wang J . The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons. Cell Rep. 2017; 20(6):1319-1334. DOI: 10.1016/j.celrep.2017.07.044. View

Sano M, Bell K, Galasko D, Galvin J, Thomas R, van Dyck C . A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011; 77(6):556-63. PMC: 3149154. DOI: 10.1212/WNL.0b013e318228bf11. View

Malpass K . Neurodevelopmental disorders: Unsilencing dormant Ube3a--hope for Angelman syndrome?. Nat Rev Neurol. 2012; 8(2):62. DOI: 10.1038/nrneurol.2012.2. View

Whittle N, Singewald N . HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?. Biochem Soc Trans. 2014; 42(2):569-81. PMC: 3961057. DOI: 10.1042/BST20130233. View

10.

Mews P, Donahue G, Drake A, Luczak V, Abel T, Berger S . Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature. 2017; 546(7658):381-386. PMC: 5505514. DOI: 10.1038/nature22405. View

11.

Ramamoorthy S, Nawaz Z . E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors. Nucl Recept Signal. 2008; 6:e006. PMC: 2329825. DOI: 10.1621/nrs.06006. View

12.

Jiang Y, Armstrong D, Albrecht U, Atkins C, Noebels J, Eichele G . Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 1998; 21(4):799-811. DOI: 10.1016/s0896-6273(00)80596-6. View

13.

Mulherkar S, Jana N . Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome. Neurobiol Dis. 2010; 40(3):586-92. DOI: 10.1016/j.nbd.2010.08.002. View

14.

Matsuura T, Sutcliffe J, Fang P, Galjaard R, Jiang Y, Benton C . De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet. 1997; 15(1):74-7. DOI: 10.1038/ng0197-74. View

15.

Stivaros S, Garg S, Tziraki M, Cai Y, Thomas O, Mellor J . Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA). Mol Autism. 2018; 9:12. PMC: 5824534. DOI: 10.1186/s13229-018-0190-z. View

16.

Lin Y, Lin J, Chou C, Chang Y, Yeh S, Chen C . Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2. Cancer Res. 2008; 68(7):2375-83. DOI: 10.1158/0008-5472.CAN-07-5807. View

17.

Huang H, Allen J, Mabb A, King I, Miriyala J, Taylor-Blake B . Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. 2011; 481(7380):185-9. PMC: 3257422. DOI: 10.1038/nature10726. View

18.

Penney J, Tsai L . Histone deacetylases in memory and cognition. Sci Signal. 2014; 7(355):re12. DOI: 10.1126/scisignal.aaa0069. View

19.

Jamal I, Kumar V, Vatsa N, Shekhar S, Singh B, Sharma A . Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome. Neurobiol Dis. 2017; 105:99-108. DOI: 10.1016/j.nbd.2017.05.010. View

20.

Li W, Cui Y, Kushner S, Brown R, Jentsch J, Frankland P . The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol. 2005; 15(21):1961-7. DOI: 10.1016/j.cub.2005.09.043. View