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DJ-1 (PARK7) was first identified as an oncogene that represses PTEN and thus induces proliferation in certain types of cancer [1]. Later, it was found that loss of DJ-1 leads to early onset of Parkinson's disease, characterised by a loss of dopaminergic neurons in the midbrain [2]. Even after more than a decade of intense research, the exact cellular function of DJ-1 is still elusive. Two hallmarks of DJ-1 are scavenging of reactive oxygen species (ROS) and its relation to mitochondria, a hub for central metabolism. Even though highly proliferating cancer cells and post-mitotic neurons are very different cell types, they have a common challenge: balancing ROS, derived from high metabolic burden. In a recent study by our lab, we investigated the role of DJ-1 on cellular metabolism in post-mitotic human neurons derived from the midbrain [3]. In line with the common observation of increased sensitivity to ROS, we observed an increased GSSG (oxidised glutathione) to GSH (reduced glutathione) ratio and increased sensitivity to the ROS inducing compound 6-hydroxydopamine, an oxidation product of dopamine. Our results suggest that altered glutamine and serine metabolism might be the metabolic cause for the observed changes in GSH homeostasis. Glutathione consists of the three amino acids glutamate, glycine and cysteine. Glutamate is derived from glutamine and glycine and cysteine can be derived from serine by the activity of serine hydroxymethyltransferase (SHMT) and via the transsulfuration pathway, respectively. The SHMT reaction also fuels the folate mediated one-carbon (1C) metabolism by donating carbon three of serine to tetrahydrofolate (THF). 5,10-methylene-THF can then be oxidised to formate via the folate cycle. Depending on the enzyme isoform and the compartment, this oxidation is NADP + or NAD + dependent, providing additional reducing potential to the cell [4]. While NADPH can be used to reduce GSSG back to GSH, NADH can be oxidised via oxidative phosphorylation to generate ATP. Our work provides a comprehensive overview of the effects of loss of DJ1 on central metabolism in non-proliferating neuronal cells and points to key metabolic steps that are crucial for cellular ROS homeostasis. However, the mechanistic link, how DJ-1 controls glutamine and serine-1C metabolism is still under investigation. In cancer cells, the serine synthesis pathway (SSP) and cellular antioxidant responses are, amongst others, controlled by NRF2 that can be stabilised by DJ-1 [5]. However, we observed that NRF2 is in very low abundance in our neuronal cell model. This is …

DJ1 at the interface between neuro-degeneration and cancer