Prasad, Renuka Jung, Hwajin Tan, Anderson Song, Yonghee Moon, Sungho Shaker, Mohammed R. Sun, Woong Lee, Junghee Ryu, Hoon Lim, Hyun Kook Jho, Eek-hoon 2024-01-19T13:33:37Z 2024-01-19T13:33:37Z 2022-01-10 2021-10 2045-2322 https://pubs.kist.re.kr/handle/201004/116314 Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and behavioral changes. Extracellular deposition of amyloid plaques (A beta) and intracellular deposition of neurofibrillary tangles in neurons are the major pathogenicities of AD. However, drugs targeting these therapeutic targets are not effective. Therefore, novel targets for the treatment of AD urgently need to be identified. Expression of the mesoderm-specific transcript (Mest) is regulated by genomic imprinting, where only the paternal allele is active for transcription. We identified hypermethylation on the Mest promoter, which led to a reduction in Mest mRNA levels and activation of Wnt signaling in brain tissues of AD patients. Mest knockout (KO) using the CRIPSR/Cas9 system in mouse embryonic stem cells and P19 embryonic carcinoma cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing shMest or inducible KO system causes neurodegeneration. Notably, depletion of Mest in primary cortical neurons of rats leads to tau phosphorylation at the S199 and T231 sites. Overall, our data suggest that hypermethylation of the Mest promoter may cause or facilitate the progression of AD. English Nature Publishing Group Hypermethylation of Mest promoter causes aberrant Wnt signaling in patients with Alzheimer's disease Article 10.1038/s41598-021-99562-9 1 Scientific Reports, v.11, no.1 Scientific Reports 11 1 Y scie scopus 000705243600008 2-s2.0-85116824251 Multidisciplinary Sciences Science & Technology - Other Topics Article SEQUENCE VARIANTS GENE NEURODEGENERATION IDENTIFICATION INHIBITION PEG1/MEST BEHAVIOR PATHWAY CATENIN CELLS Hypermethylation Mest promoter aberrant Wnt signaling