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.