Amyloid β‐induced elevation of O‐GlcNAcylated c‐Fos promotes neuronal cell death

• Published in: Aging cell 2019-02, Vol.18 (1), p.e12872-n/a
• Main Authors: Choi, Heesun, Kim, Chaeyoung, Song, Hyundong, Cha, Moon‐Yong, Cho, Hyun Jin, Son, Sung Min, Kim, Haeng Jun, Mook‐Jung, Inhee
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Animals; Apoptosis; Bcl-2-Like Protein 11 - genetics; Bcl-2-Like Protein 11 - metabolism; beta-N-Acetylhexosaminidases - metabolism; Biochemistry; Cell death; Cell Death - drug effects; Cell Line; c‐Fos; Gene Expression Regulation - drug effects; Glucosamine; Glucose metabolism; Glycosylation - drug effects; Humans; Mice, Transgenic; Nervous system diseases; Neurodegenerative diseases; neuronal cell death; Neurons - drug effects; Neurons - pathology; O-GlcNAcylation; Original; O‐linked β‐N‐acetyl glucosamine (O‐GlcNAc); Pathogenesis; Physiological aspects; Protein Stability - drug effects; Proteins; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Rats, Sprague-Dawley; Serine; Transcription; Transcription, Genetic - drug effects; β‐amyloid (Aβ)
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12872

Alzheimer's disease (AD) is an age‐related neurodegenerative disease characterized by progressive memory loss resulting from cumulative neuronal cell death. O‐linked β‐N‐acetyl glucosamine (O‐GlcNAc) modification of the proteins reflecting glucose metabolism is altered in the brains of patients with AD. However, the link between altered O‐GlcNAc modification and neuronal cell death in AD is poorly understood. Here, we examined the regulation of O‐GlcNAcylation of c‐Fos and the effects of O‐GlcNAcylated c‐Fos on neuronal cell death during AD pathogenesis. We found that amyloid beta (Aβ)‐induced O‐GlcNAcylation on serine‐56 and 57 of c‐Fos was resulted from decreased interaction between c‐Fos and O‐GlcNAcase and promoted neuronal cell death. O‐GlcNAcylated c‐Fos increased its stability and potentiated the transcriptional activity through higher interaction with c‐Jun, resulting in induction of Bim expression leading to neuronal cell death. Taken together, Aβ‐induced O‐GlcNAcylation of c‐Fos plays an important role in neuronal cell death during the pathogenesis of AD.