期刊
NUCLEIC ACIDS RESEARCH
卷 45, 期 4, 页码 2029-2039出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkw847
关键词
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资金
- Science Foundation Ireland [07/RFP/BIMF318]
- Commercialisation Fund from Enterprise Ireland [CF/2011/1603]
- Health Research Board Ph.D. studentship [HRB-PHD/2007/09]
- Irish Cancer Society [CRS11FER]
- School of Chemistry, Trinity College Dublin
- Science Foundation Ireland (SFI) [07/RFP/BIMF318] Funding Source: Science Foundation Ireland (SFI)
Queuine is a modified pyrrolopyrimidine nucleobase derived exclusively from bacteria. It posttranscriptionally replaces guanine 34 in transfer RNA isoacceptors for Asp, Asn, His and Tyr, in almost all eukaryotic organisms, through the activity of the ancient tRNA guanine transglycosylase (TGT) enzyme. tRNA hypomodification with queuine is a characteristic of rapidly-proliferating, non-differentiated cells. Autoimmune diseases, including multiple sclerosis, are characterised by the rapid expansion of T cells directed to self-antigens. Here, we demonstrate the potential medicinal relevance of targeting the modification of tRNA in the treatment of a chronic multiple sclerosis model-murine experimental autoimmune encephalomyelitis. Administration of a de novo designed eukaryotic TGT substrate (NPPDAG) led to an unprecedented complete reversal of clinical symptoms and a dramatic reduction of markers associated with immune hyperactivation and neuronal damage after five daily doses. TGT is essential for the therapeutic effect, since animals deficient in TGT activity were refractory to therapy. The data suggest that exploitation of the eukaryotic TGT enzyme is a promising approach for the treatment of multiple sclerosis.
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