Development of a brain-penetrant G9a methylase inhibitor to target Alzheimer’s disease-associated proteopathology
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.
Authors
- Guo‐li Ming (ORCID: https://orcid.org/0000-0002-2517-6075)
- Brent Asrican (ORCID: https://orcid.org/0000-0003-3434-9852)
- Hongjun Song (ORCID: https://orcid.org/0000-0002-8720-5310)
- Jing Liu (ORCID: https://orcid.org/0000-0003-4740-243X)
- Yan‐Jia Luo (ORCID: https://orcid.org/0000-0002-1288-438X)
- Juan Song (ORCID: https://orcid.org/0000-0002-7836-343X)
- Jian Jun Jin (ORCID: https://orcid.org/0000-0002-2387-3862)
- Zhexing Wen (ORCID: https://orcid.org/0000-0002-1518-3845)
- Luis Quintanilla (ORCID: https://orcid.org/0000-0001-9535-1249)
- Leon G. Coleman (ORCID: https://orcid.org/0000-0003-1693-3799)
- John A. Wrobel (ORCID: https://orcid.org/0000-0002-5828-9359)
- Ping Dong (ORCID: https://orcid.org/0000-0002-6640-6607)
- Kwang‐Su Park (ORCID: https://orcid.org/0000-0002-1910-3937)
- Mohanish Deshmukh (ORCID: https://orcid.org/0000-0002-2597-5862)
- Ryan N. Sheehy (ORCID: https://orcid.org/0000-0001-8212-5357)
- Julia Velez (ORCID: https://orcid.org/0000-0003-2448-7848)
- Adil Muneer (ORCID: https://orcid.org/0000-0002-8605-3351)
- Yongyi Li (ORCID: https://orcid.org/0009-0009-1001-3095)
- Yadong Li (ORCID: https://orcid.org/0000-0002-5977-8760)
- Feng Zhang (ORCID: https://orcid.org/0000-0003-2887-8184)
- Xian Chen (ORCID: https://orcid.org/0000-0002-8358-1247)
- Ling Xie (ORCID: https://orcid.org/0000-0003-2943-3080)
- Yan Xiong (ORCID: https://orcid.org/0000-0001-5507-6991)
- Chongchong Xu (ORCID: https://orcid.org/0000-0002-9867-9220)
- Corina Damian
Institutions
- University of North Carolina at Chapel Hill (US)
- Emory University (US)
- University of Pennsylvania (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1038/s41467-025-59128-z
- Citations
- 6
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institutes of Health
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill