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000165570 037__ $$aDZNE-2022-01710
000165570 041__ $$aEnglish
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000165570 1001_ $$aKim, Yoon A$$b0
000165570 245__ $$aRNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation.
000165570 260__ $$aHeidelberg$$bSpringer$$c2023
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000165570 520__ $$aEpitranscriptomic regulation adds a layer of post-transcriptional control to brain function during development and adulthood. The identification of RNA-modifying enzymes has opened the possibility of investigating the role epitranscriptomic changes play in the disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is one of the few known brain-enriched methyltransferases able to methylate mammalian non-coding RNAs. NSun2 loss of function due to autosomal-recessive mutations has been associated with neurological abnormalities in humans. Here, we show NSun2 is expressed in adult human neurons in the hippocampal formation and prefrontal cortex. Strikingly, we unravel decreased NSun2 protein expression and an increased ratio of pTau/NSun2 in the brains of patients with Alzheimer's disease (AD) as demonstrated by Western blotting and immunostaining, respectively. In a well-established Drosophila melanogaster model of tau-induced toxicity, reduction of NSun2 exacerbated tau toxicity, while overexpression of NSun2 partially abrogated the toxic effects. Conditional ablation of NSun2 in the mouse brain promoted a decrease in the miR-125b m6A levels and tau hyperphosphorylation. Utilizing human induced pluripotent stem cell (iPSC)-derived neuronal cultures, we confirmed NSun2 deficiency results in tau hyperphosphorylation. We also found that neuronal NSun2 levels decrease in response to amyloid-beta oligomers (AβO). Notably, AβO-induced tau phosphorylation and cell toxicity in human neurons could be rescued by overexpression of NSun2. Altogether, these results indicate that neuronal NSun2 deficiency promotes dysregulation of miR-125b and tau phosphorylation in AD and highlights a novel avenue for therapeutic targeting.
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000165570 650_7 $$2Other$$aAlzheimer’s disease
000165570 650_7 $$2Other$$aMethylation
000165570 650_7 $$2Other$$aMicroRNA
000165570 650_7 $$2Other$$aNSun2
000165570 650_7 $$2Other$$aNeurodegeneration
000165570 650_7 $$2Other$$aTau phosphorylation
000165570 650_2 $$2MeSH$$aMice
000165570 650_2 $$2MeSH$$aAnimals
000165570 650_2 $$2MeSH$$aHumans
000165570 650_2 $$2MeSH$$aAdult
000165570 650_2 $$2MeSH$$aMethyltransferases: genetics
000165570 650_2 $$2MeSH$$aPhosphorylation: genetics
000165570 650_2 $$2MeSH$$aDrosophila melanogaster: genetics
000165570 650_2 $$2MeSH$$aDrosophila melanogaster: metabolism
000165570 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000165570 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000165570 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000165570 650_2 $$2MeSH$$aMicroRNAs: genetics
000165570 650_2 $$2MeSH$$atau Proteins: metabolism
000165570 650_2 $$2MeSH$$aMammals: metabolism
000165570 7001_ $$0P:(DE-2719)2812737$$aSiddiqui, Tohid$$b1$$udzne
000165570 7001_ $$aBlaze, Jennifer$$b2
000165570 7001_ $$0P:(DE-2719)2811286$$aCosacak, Mehmet Ilyas$$b3$$udzne
000165570 7001_ $$aWinters, Tristan$$b4
000165570 7001_ $$aKumar, Atul$$b5
000165570 7001_ $$aTein, Ellen$$b6
000165570 7001_ $$aSproul, Andrew A$$b7
000165570 7001_ $$aTeich, Andrew F$$b8
000165570 7001_ $$aBartolini, Francesca$$b9
000165570 7001_ $$aAkbarian, Schahram$$b10
000165570 7001_ $$0P:(DE-2719)2811030$$aKizil, Caghan$$b11$$udzne
000165570 7001_ $$00000-0001-6487-8857$$aHargus, Gunnar$$b12
000165570 7001_ $$00000-0003-2801-5020$$aSanta-Maria, Ismael$$b13
000165570 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-022-02511-7$$gVol. 145, no. 1, p. 29 - 48$$n1$$p29 - 48$$tActa neuropathologica$$v145$$x0001-6322$$y2023
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