Downregulation of m6A Methyltransferase in the Hippocampus of Tyrobp -/- Mice and Implications for Learning and Memory Deficits

• Published in: Frontiers in neuroscience Vol. 16; p. 739201
• Main Authors: Lv, Zhanyun, Xu, Tongxiao, Li, Ran, Zheng, Dejie, Li, Yanxin, Li, Wei, Yang, Yan, Hao, Yanlei
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 21-03-2022; Frontiers Media S.A
• Subjects: 3' Untranslated regions; Adenosine; Aging; ALKBH5; Alzheimer's disease; Amyloid; Animal models; Biotechnology; Codons; Experiments; Genes; Hippocampus; Immunoprecipitation; Kinases; Learning; m6A methylation; Memory; Methylation; Methyltransferase; METTL14; METTL3; Monoclonal antibodies; mRNA; Mutation; N6-methyladenosine; Nasu-Hakola disease; Neurodegenerative diseases; Neuroscience; Protein kinase; Proteins; Rodents; Tau protein; Tyrobp–/– mice; WTAP; United States > US; China; FTO; m6A methylation; ALKBH5; METTL14; Tyrobp–/– mice; WTAP; METTL3; MeRIP-seq
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2022.739201

Loss-of-function mutations in the gene that encodes TYRO protein kinase-binding protein (
) cause Nasu-Hakola disease, a heritable disease resembling Alzheimer's disease (AD). Methylation of N6 methyl-adenosine (m6A) in mRNA plays essential roles in learning and memory. Aberrant m6A methylation has been detected in AD patients and animal models. In the present study,
mice showed learning and memory deficits in the Morris water maze, which worsened with age.
mice also showed elevated levels of total tau, Ser202/Thr205-phosphorylated tau and amyloid β in the hippocampus and cerebrocortex, which worsened with aging. The m6A methyltransferase components METTL3, METTL14, and WTAP were downregulated in
mice, while expression of demethylases that remove the m6A modification (e.g., FTO and ALKBH5) were unaltered. Methylated RNA immunoprecipitation sequencing identified 498 m6A peaks that were upregulated in
mice, and 312 m6A peaks that were downregulated. Bioinformatic analysis suggested that most of these m6A peaks occur in sequences near stop codons and 3'-untranslated regions. These findings suggest an association between m6A RNA methylation and pathological TYROBP deficiency.