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

Zhanyun Lv; Tongxiao Xu; Ran Li; Dejie Zheng; Yanxin Li; Wei Li; Yan Yang; Yanlei Hao

doi:10.3389/fnins.2022.739201

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

Front Neurosci. 2022 Mar 21:16:739201. doi: 10.3389/fnins.2022.739201. eCollection 2022.

Authors

Zhanyun Lv^{1

2}, Tongxiao Xu³, Ran Li⁴, Dejie Zheng⁵, Yanxin Li⁶, Wei Li³, Yan Yang^{3

7}, Yanlei Hao^{3

7}

Affiliations

¹ Zhejiang University Medical Center, Hangzhou, China.
² School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
³ College of Clinical Medicine, Jining Medical University, Jining, China.
⁴ Cheeloo College of Medicine, Shandong University, Jinan, China.
⁵ Health Management Center, Weifang People's Hospital, Weifang, China.
⁶ Department of Neurology, Pingdu People's Hospital, Qingdao, China.
⁷ Department of Neurology, The Affiliated Hospital of Jining Medical University, Jining, China.

Abstract

Loss-of-function mutations in the gene that encodes TYRO protein kinase-binding protein (TYROBP) 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, Tyrobp^-/- mice showed learning and memory deficits in the Morris water maze, which worsened with age. Tyrobp^-/- 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 Tyrobp^-/- 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 Tyrobp^-/- 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.

Keywords: ALKBH5; FTO; METTL14; METTL3; MeRIP-seq; Tyrobp–/– mice; WTAP; m6A methylation.