In vivo modification of tRNA with an artificial nucleobase leads to full disease remission in an animal model of multiple sclerosis
| Autor: | Colm Cunningham, Vincent P. Kelly, Sreeja Varghese, Claire Fergus, Franciane Chevot, Michelle Cotter, Kingston H. G. Mills, John M. Southern, Stephen J. Connon |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Encephalomyelitis Autoimmune Experimental Multiple Sclerosis Guanine Pyrimidinones Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system RNA Transfer In vivo Genetics medicine Animals Pyrroles Pentosyltransferases Thioguanine chemistry.chemical_classification Multiple sclerosis Experimental autoimmune encephalomyelitis Brain Queuine Genetic Therapy medicine.disease 3. Good health Mice Inbred C57BL Disease Models Animal 030104 developmental biology Enzyme chemistry Biochemistry Transfer RNA RNA 030217 neurology & neurosurgery |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | Queuine is a modified pyrrolopyrimidine nucleobase derived exclusively from bacteria. It post-transcriptionally 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. |
| Databáze: | OpenAIRE |
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