Neurodegeneration

In need of nucleosides

Nat. Cell Biol. doi:10.1038/ncb2901

Parkinson's disease (PD) is a progressive neurological disorder that results in the loss of dopaminergic neurons and has been associated with mitochondrial defects. Mutations in PTEN-induced kinase 1 (PINK1), which is linked to early-onset PD, also disrupts mitochondrial homeostasis, but the identity of the metabolic pathways that are altered remained unknown. Tufi et al. performed microarray analysis on Drosophila pink1 mutants and observed increased transcripts for genes involved in nucleotide biosynthesis and salvaging. In particular, deoxyribonucleoside kinase (dNK), which converts deoxyribonucleosides (dNs) into their monophosphate forms, was upregulated in pink1 mutants. Ubiquitous expression of dNK increased mitochondrial biogenesis and DNA synthesis, resulting in greater production of ATP and increased oxygen consumption. Neuronal overexpression of dNK was sufficient to prevent the loss of dopaminergic neurons and rescued a large majority of mitochondrial defects and motor impairments observed in pink1 mutants. Finally, pink1-mutant flies fed a diet of either dNs or folic acid exhibited an increase in nucleotide metabolism that could rescue both mitochondrial and neuronal defects. Application of dNs or folic acid to PINK1-knockdown human neuroblastoma cells also restored mitochondrial membrane potential and improved respiration. This work implicates nucleotide metabolism as an important response pathway that can protect against neurodegeneration.

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Miura, G. In need of nucleosides. Nat Chem Biol 10, 169 (2014). https://doi.org/10.1038/nchembio.1469

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