RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation

• DOI: 10.1007/s00401-022-02511-7
• Publication Date: 2022-11-10T21:14:28Z
• Authors: Yoon A. Kim; Tohid Siddiqui; Jennifer Blaze; Mehmet Ilyas Cosacak; Tristan Winters; Atul Kumar; Ellen Tein; Andrew A. Sproul; Andrew F. Teich; Francesca Bartolini; Schahram Akbarian; Caghan Kizil; Gunnar Hargus; Ismael Santa-Maria
• Keywords: Adult; 0301 basic medicine; Induced Pluripotent Stem Cells; genetics [Alzheimer Disease]; Tau phosphorylation; tau Proteins; NSun2; Methylation; Mice; 03 medical and health sciences; Alzheimer Disease; metabolism [Drosophila melanogaster]; Animals; Humans; ddc:610; genetics [MicroRNAs]; Neurodegeneration; Phosphorylation; genetics [Phosphorylation]; Mammals; genetics [Drosophila melanogaster]; Original Paper; metabolism [Mammals]; MicroRNA; Methyltransferases; metabolism [tau Proteins]; 3. Good health; metabolism [Induced Pluripotent Stem Cells]; MicroRNAs; Drosophila melanogaster; genetics [Methyltransferases]; Alzheimer’s disease; metabolism [Alzheimer Disease]

Epitranscriptomic regulation adds a layer of post-transcriptional control to brain function during development and adulthood. The identification RNA-modifying enzymes has opened the possibility investigating role epitranscriptomic changes play in disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is one few known brain-enriched methyltransferases able methylate mammalian non-coding RNAs. NSun2 loss due autosomal-recessive mutations been associated with neurological abnormalities humans. Here, we show expressed adult human neurons hippocampal formation prefrontal cortex. Strikingly, unravel decreased protein expression an increased ratio pTau/NSun2 brains patients Alzheimer's (AD) as demonstrated by Western blotting immunostaining, respectively. In well-established Drosophila melanogaster model tau-induced toxicity, reduction exacerbated tau while overexpression partially abrogated toxic effects. Conditional ablation mouse promoted decrease miR-125b m6A levels hyperphosphorylation. Utilizing induced pluripotent stem cell (iPSC)-derived neuronal cultures, confirmed deficiency results We also found that response amyloid-beta oligomers (AβO). Notably, AβO-induced phosphorylation toxicity could be rescued NSun2. Altogether, these indicate promotes dysregulation AD highlights novel avenue for therapeutic targeting.