Journal Article

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

Stefano Bartesaghi, Joanne Betts-Henderson, Kelvin Cain, David Dinsdale, Xiaoshan Zhou, Anna Karlsson, Paolo Salomoni and Pierluigi Nicotera

in Human Molecular Genetics

Volume 19, issue 9, pages 1669-1677
Published in print May 2010 | ISSN: 0964-6906
Published online February 2010 | e-ISSN: 1460-2083 | DOI:
Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration

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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.

Journal Article.  4515 words.  Illustrated.

Subjects: Genetics and Genomics

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