Loss of Parkinson Disease Protein 7 (PARK7) upregulates ROS and cell migration and is associated with recurrent pregnancy loss.

BACKGROUND

Successful implantation is dependent on a synchronous dialogue between several proteins that act to control cellular dynamics including actin and microtubule reorganisation and cell motility. An impaired crosstalk can lead to complications including recurrent pregnancy loss (RPL) though the precise mechanisms remain unclear. Parkinson disease protein 7 (PARK7; encoding DJ-1), characterised for its participation in neurodegeneration, has emerged as a novel cytoskeletal and antioxidant regulator however, the role of DJ-1 in early pregnancy is unknown.

METHODS

We employed systems biology approaches and functional studies in both human and murine models to examine the expression and role of DJ-1 during the window of implantation. LC–MS/MS proteomics analysis was conducted to identify proteins with differential expression between decidualized endometrial stromal cells (EnSC) with and without DJ-1 knockdown. Further, DJ-1 expression was manipulated using loss and gain of function strategies to investigate its impact on reactive oxygen species (ROS), the actin cytoskeleton and cellular motility. Lastly, knockdown of Palladin (a key actin regulator) and overexpression of Glutathione peroxidase 3 (GPX3) were used to investigate the downstream effects.

RESULTS

Endometrial DJ-1 had the highest expression during the implantation window and loss of DJ-1 was associated with pregnancy loss in both humans and mice. The proteomics data revealed dysregulation of cytoskeletal protein, Palladin and antioxidant enzymes. Knockdown of DJ-1 using siRNA led to elevated ROS levels, increased actin polymerisation and resulted in increased cell motility towards aneuploidic signals. Conversely, DJ-1 overexpression led to the reversal of these effects. Moreover, knockdown of downstream target Palladin restored abnormal actin polymerization and prevented cell motility towards aneuploidic chemotactic signals. Further, overexpression of GPX3 mitigated ROS production and restored cell migration.

CONCLUSIONS

Taken together, our findings identified an unexpected function of the DJ-1-Palladin axis in the endometrium and its function as a redox-sensitive chaperone and in cytoskeleton remodelling and migration. Thus, uncoupling of this axis may result in adverse pregnancy complications including recurrent pregnancy loss.