Xian Chen, Ling Xie, Ryan Sheehy, Yan Xiong, Adil Muneer, John Wrobel, Kwang-Su Park, Jing Liu, Julia Velez, Yanjia Luo, Ya-Dong Li, Luis Quintanilla, Yongyi Li, Chongchong Xu, Zhexing Wen, Juan Song, Jian Jin, Mohanish Deshmukh
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...
November 21, 2023: Research Square