Development of a brain-penetrant G9a methylase inhibitor to target Alzheimer’s disease-associated proteopathology
Year: 2025
Type: article
Abstract: Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects. One-Sentence Summary: A brain-penetrant inhibitor of G9a methylase blocks G9a translational mechanism to reverse Alzheimer's disease related proteome for effective therapy.
Source: Nature Communications
Authors: 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 Quintanilla, Yongyi Li, Chongchong Xu, Mohanish Deshmukh, Leon G. Coleman, Guo-Li Ming, Hongjun Song, Zhexing Wen, Jian Jin, Juan Song, Xian Chen
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, National Institutes of Health, University of North Carolina at Chapel Hill, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G107414137, Novel brain-penetrant drugs for translation-targeting therapeutics of Alzheimer’s disease, G1267525135, Sex-dependent role of 5HT1A receptors in adult neurogenesis and hippocampal function, An AVANCE NEO 600 MHz NMR Spectrometer System for Structural and Chemical Biology, G176670597, G2039702874, G2640097755, G272537366, G2992257184, G3440148905, G3942228346, G4574288286, G4736828791, Novel therapeutic intervention of early-stage T1D, G5832817453, Deciphering the non-canonical function of the histone methyltransferase G9a in the etiology of AD, G6432965905, Elucidate the roles of Alzheimer's disease risk genes and variants in gene expression and AD-related phenotypes, G7056193313, Microglia Activation and TLR-induced Neurodegeneration by Alcohol Promotes Progression of Alzheimer Pathology, G7691555271, An AVANCE NEO 400 MHz NMR Spectrometer for Chemical Biology and Drug Discovery, G8361476032, G9000017028, G9000081607, G9000093196, G9000097063, G9000098983, G9000215912, G9000282006, Continuous Neurogenesis in the Mammalian Hippocampus
OpenAlex ID: W4410108790