Chemical Probe To Monitor the Parkinsonism-Associated Protein DJ‑1 in Live Cells

Reactive oxygen species (ROS) play
an important role in the onset of Parkinson’s disease (PD),
and deciphering protective mechanisms is a major goal for therapeutic
development. Here, DJ-1 (PARK7) gained major attention when a conserved
cysteine residue with a putative role in oxidative stress sensing/protection
was linked to PD. Inspired by previous studies with a bacterial homologue
of DJ-1, several amino-epoxycylcohexenones were screened for enzyme
inhibition, and a chemical probe with specificity for the human ortholog
was selected for cellular studies. The probe selectively labeled the
cysteine oxidation sensor and whole proteome analysis in HeLa, A549,
and SHSY5Y cell lines confirmed strong enrichment of reduced DJ-1
as the most prominent target. Increasing levels of oxidative stress
diminished this signal demonstrating the utility of our tool compound
for selective in situ monitoring of this important
biomarker in its reduced state.