Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism

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2016
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Meiser, Johannes
Delcambre, Sylvie
Wegner, André
Jäger, Christian
Ghelfi, Jenny
Fouquier d'Herouel, Aymeric
Dong, Xiangyi
Hiller, Karsten
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Neurobiology of Disease. 2016, 89, pp. 112-125. ISSN 0969-9961. eISSN 1095-953X. Available under: doi: 10.1016/j.nbd.2016.01.019
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The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches.

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ISO 690MEISER, Johannes, Sylvie DELCAMBRE, André WEGNER, Christian JÄGER, Jenny GHELFI, Aymeric FOUQUIER D'HEROUEL, Xiangyi DONG, Stefan SCHILDKNECHT, Marcel LEIST, Karsten HILLER, 2016. Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism. In: Neurobiology of Disease. 2016, 89, pp. 112-125. ISSN 0969-9961. eISSN 1095-953X. Available under: doi: 10.1016/j.nbd.2016.01.019
BibTex
@article{Meiser2016impai-34007,
  year={2016},
  doi={10.1016/j.nbd.2016.01.019},
  title={Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism},
  volume={89},
  issn={0969-9961},
  journal={Neurobiology of Disease},
  pages={112--125},
  author={Meiser, Johannes and Delcambre, Sylvie and Wegner, André and Jäger, Christian and Ghelfi, Jenny and Fouquier d'Herouel, Aymeric and Dong, Xiangyi and Schildknecht, Stefan and Leist, Marcel and Hiller, Karsten}
}
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