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Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency
- Source :
- Annals of Neurology. 81:641-652
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
Abstract
- Objective Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2–/–) mice by 2- to 3-fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: (1) deoxynucleosides might be the major active agents and (2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy. Methods To test these hypotheses, we assessed two therapies in Tk2–/– mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP. Results We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2–/– animals compared to dCMP+dTMP. Interpretation Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641–652
- Subjects :
- 0301 basic medicine
chemistry.chemical_classification
Catabolism
Deamination
Deoxycytidine monophosphate
Biology
Molecular biology
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
Enzyme
Neurology
chemistry
Thymidine kinase
Deoxycytidine
Neurology (clinical)
Tetrahydrouridine
Thymidine
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 03645134
- Volume :
- 81
- Database :
- OpenAIRE
- Journal :
- Annals of Neurology
- Accession number :
- edsair.doi...........2fdba75571dc2e1a61473844dd35a262