Regulation of metabolism and immune response via DJ-1 defines human astrocytic cell fate in Parkinson's disease and Glioblastoma

Pauline Mencke, Jochen Ohnmacht, Félicia Jeannelle, Adrien J Ries, Mónica Miranda de la Maza, Mathilde Ullrich, François Massart, Patrycja Mulica, Katja Badanjak, Zoé Hanss, Arkadiusz Rybicki, Paul Antony, Sylvie Delcambre, Giuseppe Arena, Gérald Cruciani, Javier Jarazo, Floriane Gavotto, Christian Jäger, Anouk Ewen, Maria Pires Pacheco, Dirk Brenner, Jens Schwamborn, Thomas Sauter, Lasse Sinkkonen, Gunnar Dittmar, Ricardo Taipa, David Bouvier, Johannes Meiser, Anne Grünewald, Vincenzo Bonifati, Michael Platten, Rejko Krüger and Ibrahim Boussaad

An inverse correlation for the expression of Parkinson´s disease (PD)- and cancer-associated genes has been previously reported. PARK7, encoding DJ-1, was initially identified as an oncogene, but loss of DJ-1 causes early-onset PD. However, it remains elusive how differential DJ-1 levels contribute to opposite cell fates in cancer and PD. Here, we demonstrate specific and differential effects of DJ-1 protein levels in patient-derived cellular models of PD and glioblastoma (GBM) cell lines. Loss of DJ-1 protein in human astrocytes led to impairment of energy metabolism and cell growth associated with an increased immune response upon IL-1β stimulation. In contrast, elevated DJ-1 levels in DJ-1 overexpressing astrocytes and GBM cell lines had the opposite effect. We show that decreased glutathione (GSH) synthesis and therefore increased reactive oxygen species (ROS) levels underly the observed cellular phenotypes, which could be rescued by supplementation with glutathione precursors. Thus, the mechanism by which DJ-1 modulates these phenotypes is the same in both diseases.