IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-022-35749-6.html
   My bibliography  Save this article

Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model

Author

Listed:
  • Jamal B. Williams

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Qing Cao

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Wei Wang

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Young-Ho Lee

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Luye Qin

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Ping Zhong

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Yong Ren

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Kaijie Ma

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Zhen Yan

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

Abstract

Pleiotropic mechanisms have been implicated in Alzheimer’s disease (AD), including transcriptional dysregulation, protein misprocessing and synaptic dysfunction, but how they are mechanistically linked to induce cognitive deficits in AD is unclear. Here we find that the histone methyltransferase Smyd3, which catalyzes histone H3 lysine 4 trimethylation (H3K4me3) to activate gene transcription, is significantly elevated in prefrontal cortex (PFC) of AD patients and P301S Tau mice, a model of tauopathies. A short treatment with the Smyd3 inhibitor, BCI-121, rescues cognitive behavioral deficits, and restores synaptic NMDAR function and expression in PFC pyramidal neurons of P301S Tau mice. Fbxo2, which encodes an E3 ubiquitin ligase controlling the degradation of NMDAR subunits, is identified as a downstream target of Smyd3. Smyd3-induced upregulation of Fbxo2 in P301S Tau mice is linked to the increased NR1 ubiquitination. Fbxo2 knockdown in PFC leads to the recovery of NMDAR function and cognitive behaviors in P301S Tau mice. These data suggest an integrated mechanism and potential therapeutic strategy for AD.

Suggested Citation

  • Jamal B. Williams & Qing Cao & Wei Wang & Young-Ho Lee & Luye Qin & Ping Zhong & Yong Ren & Kaijie Ma & Zhen Yan, 2023. "Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35749-6
    DOI: 10.1038/s41467-022-35749-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-35749-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-35749-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Ji-Song Guan & Stephen J. Haggarty & Emanuela Giacometti & Jan-Hermen Dannenberg & Nadine Joseph & Jun Gao & Thomas J. F. Nieland & Ying Zhou & Xinyu Wang & Ralph Mazitschek & James E. Bradner & Ronal, 2009. "HDAC2 negatively regulates memory formation and synaptic plasticity," Nature, Nature, vol. 459(7243), pages 55-60, May.
    2. Caryn S. Ross-Innes & Rory Stark & Andrew E. Teschendorff & Kelly A. Holmes & H. Raza Ali & Mark J. Dunning & Gordon D. Brown & Ondrej Gojis & Ian O. Ellis & Andrew R. Green & Simak Ali & Suet-Feung C, 2012. "Differential oestrogen receptor binding is associated with clinical outcome in breast cancer," Nature, Nature, vol. 481(7381), pages 389-393, January.
    3. Brookmeyer, R. & Gray, S. & Kawas, C., 1998. "Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset," American Journal of Public Health, American Public Health Association, vol. 88(9), pages 1337-1342.
    4. Pawel K. Mazur & Nicolas Reynoird & Purvesh Khatri & Pascal W. T. C. Jansen & Alex W. Wilkinson & Shichong Liu & Olena Barbash & Glenn S. Van Aller & Michael Huddleston & Dashyant Dhanak & Peter J. Tu, 2014. "SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer," Nature, Nature, vol. 510(7504), pages 283-287, June.
    5. Vincenzo Sorrentino & Mario Romani & Laurent Mouchiroud & John S. Beck & Hongbo Zhang & Davide D’Amico & Norman Moullan & Francesca Potenza & Adrien W. Schmid & Solène Rietsch & Scott E. Counts & Joha, 2017. "Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity," Nature, Nature, vol. 552(7684), pages 187-193, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Nickole Moon & Christopher P. Morgan & Ruth Marx-Rattner & Alyssa Jeng & Rachel L. Johnson & Ijeoma Chikezie & Carmen Mannella & Mary D. Sammel & C. Neill Epperson & Tracy L. Bale, 2024. "Stress increases sperm respiration and motility in mice and men," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Yawen Lei & Yaoguang Yu & Wei Fu & Tao Zhu & Caihong Wu & Zhihao Zhang & Zewang Yu & Xin Song & Jianqu Xu & Zhenwei Liang & Peitao Lü & Chenlong Li, 2024. "BCL7A and BCL7B potentiate SWI/SNF-complex-mediated chromatin accessibility to regulate gene expression and vegetative phase transition in plants," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Yanjiang Liu & Gongcheng Hu & Shengxiong Yang & Mingze Yao & Zicong Liu & Chenghong Yan & Yulin Wen & Wangfang Ping & Juehan Wang & Yawei Song & Xiaotao Dong & Guangjin Pan & Hongjie Yao, 2023. "Functional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Ravinder K. Bahia & Xiaoguang Hao & Rozina Hassam & Orsolya Cseh & Danielle A. Bozek & H. Artee Luchman & Samuel Weiss, 2023. "Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Yong Yean Kim & Berkley E. Gryder & Ranuka Sinniah & Megan L. Peach & Jack F. Shern & Abdalla Abdelmaksoud & Silvia Pomella & Girma M. Woldemichael & Benjamin Z. Stanton & David Milewski & Joseph J. B, 2024. "KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Haoxi Chai & Harianto Tjong & Peng Li & Wei Liao & Ping Wang & Chee Hong Wong & Chew Yee Ngan & Warren J. Leonard & Chia-Lin Wei & Yijun Ruan, 2023. "ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Tulsi Patel & Jennifer Hammelman & Siaresh Aziz & Sumin Jang & Michael Closser & Theodore L. Michaels & Jacob A. Blum & David K. Gifford & Hynek Wichterle, 2022. "Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    9. Sayantani Ghosh Dastidar & Bony Kumar & Bo Lauckner & Damien Parrello & Danielle Perley & Maria Vlasenok & Antariksh Tyagi & Nii Koney-Kwaku Koney & Ata Abbas & Sergei Nechaev, 2023. "Transcriptional responses of cancer cells to heat shock-inducing stimuli involve amplification of robust HSF1 binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Qiutao Xu & Yaping Yue & Biao Liu & Zhengting Chen & Xuan Ma & Jing Wang & Yu Zhao & Dao-Xiu Zhou, 2023. "ACL and HAT1 form a nuclear module to acetylate histone H4K5 and promote cell proliferation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Konstantin Okonechnikov & Aylin Camgöz & Owen Chapman & Sameena Wani & Donglim Esther Park & Jens-Martin Hübner & Abhijit Chakraborty & Meghana Pagadala & Rosalind Bump & Sahaana Chandran & Katerina K, 2023. "3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    12. Zarish Noreen & Jessica DeJesus & Attya Bhatti & Christopher A. Loffredo & Peter John & Jahangir S. Khan & Gail Nunlee-Bland & Somiranjan Ghosh, 2018. "Epidemiological Investigation of Type 2 Diabetes and Alzheimer’s Disease in a Pakistani Population," IJERPH, MDPI, vol. 15(8), pages 1-10, July.
    13. Stanislav Tsitkov & Kelsey Valentine & Velina Kozareva & Aneesh Donde & Aaron Frank & Susan Lei & Jennifer Eyk & Steve Finkbeiner & Jeffrey D. Rothstein & Leslie M. Thompson & Dhruv Sareen & Clive N. , 2024. "Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Jing Chen & Zhen Hu & Mukta Phatak & John Reichard & Johannes M Freudenberg & Siva Sivaganesan & Mario Medvedovic, 2013. "Genome-Wide Signatures of Transcription Factor Activity: Connecting Transcription Factors, Disease, and Small Molecules," PLOS Computational Biology, Public Library of Science, vol. 9(9), pages 1-12, September.
    15. Joyce J. Thompson & Daniel J. Lee & Apratim Mitra & Sarah Frail & Ryan K. Dale & Pedro P. Rocha, 2022. "Extensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    16. Luis Filipe Costa-Machado & Esther Garcia-Dominguez & Rebecca L. McIntyre & Jose Luis Lopez-Aceituno & Álvaro Ballesteros-Gonzalez & Andrea Tapia-Gonzalez & David Fabregat-Safont & Tobias Eisenberg & , 2023. "Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    17. Junhao Li & Manoj K. Jaiswal & Jo-Fan Chien & Alexey Kozlenkov & Jinyoung Jung & Ping Zhou & Mahammad Gardashli & Luc J. Pregent & Erica Engelberg-Cook & Dennis W. Dickson & Veronique V. Belzil & Eran, 2023. "Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    18. Paola Cattaneo & Michael G. B. Hayes & Nina Baumgarten & Dennis Hecker & Sofia Peruzzo & Galip S. Aslan & Paolo Kunderfranco & Veronica Larcher & Lunfeng Zhang & Riccardo Contu & Gregory Fonseca & Sim, 2022. "DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    19. Moritz Binder & Raphael E. Szalat & Srikanth Talluri & Mariateresa Fulciniti & Hervé Avet-Loiseau & Giovanni Parmigiani & Mehmet K. Samur & Nikhil C. Munshi, 2024. "Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    20. Masataka Kikuchi & Soichi Ogishima & Tadashi Miyamoto & Akinori Miyashita & Ryozo Kuwano & Jun Nakaya & Hiroshi Tanaka, 2013. "Identification of Unstable Network Modules Reveals Disease Modules Associated with the Progression of Alzheimer’s Disease," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-1, November.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35749-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.