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Development of a brain-penetrant G9a methylase inhibitor to target Alzheimer’s disease-associated proteopathology

Author

Listed:
  • Ling Xie

    (University of North Carolina at Chapel Hill)

  • Ryan N. Sheehy

    (University of North Carolina at Chapel Hill)

  • Adil Muneer

    (University of North Carolina at Chapel Hill)

  • Yan Xiong

    (Icahn School of Medicine at Mount Sinai)

  • John A. Wrobel

    (University of North Carolina at Chapel Hill)

  • Feng Zhang

    (University of Pennsylvania)

  • Kwang-Su Park

    (Icahn School of Medicine at Mount Sinai)

  • Julia Velez

    (Icahn School of Medicine at Mount Sinai)

  • Jing Liu

    (Icahn School of Medicine at Mount Sinai)

  • Yan-Jia Luo

    (University of North Carolina at Chapel Hill)

  • Brent Asrican

    (University of North Carolina at Chapel Hill)

  • Ping Dong

    (University of North Carolina at Chapel Hill)

  • Ya-Dong Li

    (University of North Carolina at Chapel Hill)

  • Corina Damian

    (University of North Carolina at Chapel Hill)

  • Luis Quintanilla

    (University of North Carolina at Chapel Hill)

  • Yongyi Li

    (University of North Carolina at Chapel Hill)

  • Chongchong Xu

    (Emory University School of Medicine)

  • Mohanish Deshmukh

    (University of North Carolina at Chapel Hill)

  • Leon G. Coleman

    (University of North Carolina at Chapel Hill School of Medicine)

  • Guo-Li Ming

    (University of Pennsylvania)

  • Hongjun Song

    (University of Pennsylvania)

  • Zhexing Wen

    (Emory University School of Medicine)

  • Jian Jin

    (Icahn School of Medicine at Mount Sinai)

  • Juan Song

    (University of North Carolina at Chapel Hill)

  • Xian Chen

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

Abstract

Current Aβ-targeting therapeutics for Alzheimer’s disease (AD) only slow cognitive decline due to poor understanding of AD pathogenesis. Here we describe a mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of hippocampal proteins associated with AD pathology. Correspondingly, we developed a brain-penetrant inhibitor of G9a, MS1262, which restored both age-related learning & memory and noncognitive functions in multiple AD mouse models. Further, comparison of AD pathology-correlated mouse proteomes with those of AD patients found G9a regulates pathological pathways that promote Aβ and neurofibrillary tangles. This mouse-to-human overlap of G9a regulated AD-associated pathologic proteins supports at the molecular level the efficacy of targeting G9a translational mechanism for treating AD patients. Additionally, MS1262 treatment reversed the AD-characteristic expression or phosphorylation of multiple clinically validated biomarkers of AD that have the potential to be used for early-stage AD diagnosis and companion diagnosis of individualized drug effects.

Suggested Citation

  • Ling Xie & Ryan N. Sheehy & Adil Muneer & Yan Xiong & John A. Wrobel & Feng Zhang & Kwang-Su Park & Julia Velez & Jing Liu & Yan-Jia Luo & Brent Asrican & Ping Dong & Ya-Dong Li & Corina Damian & Luis, 2025. "Development of a brain-penetrant G9a methylase inhibitor to target Alzheimer’s disease-associated proteopathology," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59128-z
    DOI: 10.1038/s41467-025-59128-z
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    References listed on IDEAS

    as
    1. Zhexing Wen & Ha Nam Nguyen & Ziyuan Guo & Matthew A. Lalli & Xinyuan Wang & Yijing Su & Nam-Shik Kim & Ki-Jun Yoon & Jaehoon Shin & Ce Zhang & Georgia Makri & David Nauen & Huimei Yu & Elmer Guzman &, 2014. "Synaptic dysregulation in a human iPS cell model of mental disorders," Nature, Nature, vol. 515(7527), pages 414-418, November.
    2. Cui Liu & Yanbao Yu & Feng Liu & Xin Wei & John A. Wrobel & Harsha P. Gunawardena & Li Zhou & Jian Jin & Xian Chen, 2014. "A chromatin activity-based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing," Nature Communications, Nature, vol. 5(1), pages 1-16, December.
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