title: Transgene expression of Drosophila melanogaster nucleoside kinase reverses mitochondrial thymidine kinase 2 deficiency.
abstract: A strategy to reverse the symptoms of thymidine kinase 2 (TK2) deficiency in a mouse model was investigated. The nucleoside kinase from Drosophila melanogaster (Dm-dNK) was expressed in TK2-deficient mice that have been shown to present with a severe phenotype caused by mitochondrial DNA depletion. The Dm-dNK(+/-) transgenic mice were shown to be able to rescue the TK2-deficient mice. The Dm-dNK(+/-)TK2(-/-) mice were normal as judged by growth and behavior during the observation time of 6 months. The Dm-dNK-expressing mice showed a substantial increase in thymidine-phosphorylating activity in investigated tissues. The Dm-dNK expression also resulted in highly elevated dTTP pools. The dTTP pool alterations did not cause specific mitochondrial DNA mutations or deletions when 6-month-old mice were analyzed. The mitochondrial DNA was also detected at normal levels. In conclusion, the Dm-dNK(+/-)TK2(-/-) mouse model illustrates how dTMP synthesized in the cell nucleus can compensate for loss of intramitochondrial dTMP synthesis in differentiated tissue. The data presented open new possibilities to treat the severe symptoms of TK2 deficiency.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institute, Karolinska University Hospital, SE-14186 Huddinge, Sweden.
authors.forename: Shuba
authors.initials: S
authors.lastname: Krishnan
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Zhou
authors.forename: João A
authors.initials: JA
authors.lastname: Paredes
authors.forename: Raoul V
authors.initials: RV
authors.lastname: Kuiper
authors.forename: Sophie
authors.initials: S
authors.lastname: Curbo
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004272:DNA, Mitochondrial / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology*; D009711:Nucleotides / Q000235:genetics; D010770:Phosphotransferases / Q000378:metabolism*; D017354:Point Mutation; D013937:Thymidine Kinase / Q000378:metabolism*; D019076:Transgenes
chemical_list: D004272:DNA, Mitochondrial; D009711:Nucleotides; D010770:Phosphotransferases; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C021892:nucleoside phosphotransferase