TY  - JOUR
AU  - Kim, Yoon A
AU  - Siddiqui, Tohid
AU  - Blaze, Jennifer
AU  - Cosacak, Mehmet Ilyas
AU  - Winters, Tristan
AU  - Kumar, Atul
AU  - Tein, Ellen
AU  - Sproul, Andrew A
AU  - Teich, Andrew F
AU  - Bartolini, Francesca
AU  - Akbarian, Schahram
AU  - Kizil, Caghan
AU  - Hargus, Gunnar
AU  - Santa-Maria, Ismael
TI  - RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation.
JO  - Acta neuropathologica
VL  - 145
IS  - 1
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2022-01710
SP  - 29 - 48
PY  - 2023
AB  - 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.
KW  - Mice
KW  - Animals
KW  - Humans
KW  - Adult
KW  - Methyltransferases: genetics
KW  - Phosphorylation: genetics
KW  - Drosophila melanogaster: genetics
KW  - Drosophila melanogaster: metabolism
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - MicroRNAs: genetics
KW  - tau Proteins: metabolism
KW  - Mammals: metabolism
KW  - Alzheimer’s disease (Other)
KW  - Methylation (Other)
KW  - MicroRNA (Other)
KW  - NSun2 (Other)
KW  - Neurodegeneration (Other)
KW  - Tau phosphorylation (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9807547
C6  - pmid:36357715
DO  - DOI:10.1007/s00401-022-02511-7
UR  - https://pub.dzne.de/record/165570
ER  -