Meiser J, Delcambre S, Wegner A, Jäger C, Ghelfi J, d'Herouel A Fouquier, Dong X, Weindl D, Stautner C, Nonnenmacher Y, Michelucci A, Popp O, Giesert F, Schildknecht S, Krämer L, Schneider J G, Woitalla D, Wurst W, Skupin A, Weisenhorn D M Vogt, Krüger R, Leist M, Hiller K
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Neurobiol Dis. 2016 May;89:112-25. doi: 10.1016/j.nbd.2016.01.019. Epub 2016 Feb 1.
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.
致癌基因DJ-1最初被鉴定为PTEN的一种抑制因子。进一步研究发现，功能丧失突变是帕金森病（PD）的一个致病因素。DJ-1在细胞抗氧化反应中具有重要功能，但其在神经元中心代谢中的作用仍不清楚。我们应用稳定同位素辅助代谢谱分析来研究DJ-1功能丧失的影响，结果表明，DJ-1缺陷的神经元细胞表现出谷氨酰胺流入减少和丝氨酸生物合成降低。通过为谷胱甘肽合成提供前体，这两条代谢途径是细胞抗氧化反应的重要贡献者。由于DJ-1缺失导致这些途径的下调会导致抗氧化反应受损。此外，DJ-1缺陷的小鼠小胶质细胞表现出微弱但持续的促炎激活。中枢代谢改变和胶质细胞持续激活的综合作用增加了携带突变DJ-1的患者中多巴胺能神经元变性的易感性。我们的研究揭示了导致细胞不稳定性增加的代谢改变，并确定了潜在的新干预点，可根据新的转化医学方法进一步研究。
