Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration

Hum Mol Genet. 2010 May 1;19(9):1669-77. doi: 10.1093/hmg/ddq043. Epub 2010 Feb 1.


Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560). However, more recently, neurological phenotypes have been demonstrated in patients carrying TK2 mutations, thus suggesting that loss of TK2 results in neuronal dysfunction. Here, we directly address the role of TK2 in neuronal homeostasis using a knockout mouse model. We demonstrate that in vivo loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types. Overall, our findings demonstrate that TK2 deficiency leads to neuronal dysfunction in vivo, and have important implications for understanding the mechanisms of neurological impairment in MDS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Ataxia / enzymology
  • Ataxia / etiology
  • Base Sequence
  • Brain / metabolism
  • DNA Copy Number Variations
  • DNA, Mitochondrial / genetics
  • Energy Metabolism
  • Genetic Vectors
  • Immunoblotting
  • Immunohistochemistry
  • Lentivirus
  • Mice
  • Mice, Knockout
  • Mitochondrial Diseases / complications
  • Mitochondrial Diseases / genetics*
  • Molecular Sequence Data
  • Mutation / genetics
  • Neurons / cytology*
  • Neurons / metabolism*
  • Thymidine Kinase / deficiency*
  • Thymidine Kinase / genetics


  • DNA, Mitochondrial
  • thymidine kinase 2
  • Thymidine Kinase