RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation.
Autor: Kim, Yoon A.; Siddiqui, Tohid; Blaze, Jennifer; Ilyas Cosacak, Mehmet; Winters, Tristan; Kumar, Atul; Tein, Ellen; Sproul, Andrew A.; Teich, Andrew F.; Bartolini, Francesca; Akbarian, Schahram; Kizil, Caghan; Hargus, Gunnar; Santa-María, Ismael
Resumen: Epitranscriptomic regulation adds a layer of post-transcriptional control to brain function during development and adulthood.
The identification of RNA-modifying enzymes has opened the possibility of investigating the role epitranscriptomic
changes play in the disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is one of the few known brain-enriched
methyltransferases able to methylate mammalian non-coding RNAs. NSun2 loss of function due to autosomal-recessive
mutations has been associated with neurological abnormalities in humans. Here, we show NSun2 is expressed in adult human
neurons in the hippocampal formation and prefrontal cortex. Strikingly, we unravel decreased NSun2 protein expression
and an increased ratio of pTau/NSun2 in the brains of patients with Alzheimer’s disease (AD) as demonstrated by Western
blotting and immunostaining, respectively. In a well-established Drosophila melanogaster model of tau-induced toxicity,
reduction of NSun2 exacerbated tau toxicity, while overexpression of NSun2 partially abrogated the toxic effects. Conditional
ablation of NSun2 in the mouse brain promoted a decrease in the miR-125b m6A levels and tau hyperphosphorylation.
Utilizing human induced pluripotent stem cell (iPSC)-derived neuronal cultures, we confirmed NSun2 deficiency results
in tau hyperphosphorylation. We also found that neuronal NSun2 levels decrease in response to amyloid-beta oligomers
(AβO). Notably, AβO-induced tau phosphorylation and cell toxicity in human neurons could be rescued by overexpression
of NSun2. Altogether, these results indicate that neuronal NSun2 deficiency promotes dysregulation of miR-125b and tau
phosphorylation in AD and highlights a novel avenue for therapeutic targeting.
Identificador universal: https://hdl.handle.net/10641/3491
Fecha: 2022
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