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Keywords:

  • DJ-1;
  • dopamine;
  • microglia;
  • monoamine oxidase;
  • Parkinson's disease;
  • rasagaline

Abstract

Thumbnail image of graphical abstract

DJ-1 is an oxidative stress sensor that localizes to the mitochondria when the cell is exposed to oxidative stress. DJ-1 mutations that result in gene deficiency are linked to increased risk of Parkinson's disease (PD). Activation of microglial stress conditions that are linked to PD may result in neuronal death. We postulated that DJ-1 deficiency may increase microglial neurotoxicity. We found that down-regulation of DJ-1 in microglia using an shRNA approach increased cell sensitivity to dopamine as measured by secreted pro-inflammatory cytokines such as IL-1β and IL-6. Furthermore, we discovered that DJ-1-deficient microglia had increased monoamine oxidase activity that resulted in elevation of intracellular reactive oxygen species and nitric oxide leading to increased dopaminergic neurotoxicity. Rasagaline, a monoamine oxidase inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and significantly reduced neurotoxicity. Moreover, we discovered that DJ-1-deficient microglia have reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), previously suggested as a risk factor for pro-inflammation in neurodegenerative diseases. Further studies of DJ-1-mediated cellular pathways in microglia may contribute useful insights into the development of PD providing future avenues for therapeutic intervention.

We postulated that DJ-1 deficiency may increase microglial neurotoxicity to dopaminergic neurons. We discovered that DJ-1-deficient microglia had increased monoamine oxidase (MAO) activity that resulted in elevation of intracellular reactive oxygen species, nitric oxide, and pro-inflammatory cytokines, leading to increased dopaminergic neurotoxicity. Rasagaline, an MAO inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and neurotoxicity.