Journal Article

DZNE-2022-01710

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation.

Kim, Y. A. ; Siddiqui, T.DZNE* ; Blaze, J. ; Cosacak, M. I.DZNE* ; Winters, T. ; Kumar, A. ; Tein, E. ; Sproul, A. A. ; Teich, A. F. ; Bartolini, F. ; Akbarian, S. ; Kizil, C.DZNE* ; Hargus, G. ; Santa-Maria, I.

2023
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-022-02511-7

Abstract: 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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Adult (MeSH) ; Methyltransferases: genetics (MeSH) ; Phosphorylation: genetics (MeSH) ; Drosophila melanogaster: genetics (MeSH) ; Drosophila melanogaster: metabolism (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; MicroRNAs: genetics (MeSH) ; tau Proteins: metabolism (MeSH) ; Mammals: metabolism (MeSH) ; Alzheimer’s disease ; Methylation ; MicroRNA ; NSun2 ; Neurodegeneration ; Tau phosphorylation

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Contributing Institute(s):

1. Mechanisms of induced plasticity of the vertebrate brain (AG Kizil)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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