URB597 downregulates DJ-1 expression in the mouse striatum and induces neurodegeneration.

DJ-1 is a multifunctional protein involved in diverse cellular processes, including defense against oxidative stress, regulation of gene transcription, and maintenance of mitochondrial function. Mutations in the DJ-1 gene are closely associated with early-onset Parkinson's disease, and loss of DJ-1 function increases the susceptibility of dopaminergic neurons to oxidative damage, potentially driving neurodegeneration. Therefore, DJ-1 represents an attractive therapeutic target for PD. In this study, we screened a library of blood-brain barrier-permeable small molecules to identify compounds that modulate DJ-1 expression in the mouse brain. Through molecular docking, we discovered that URB597, a selective fatty acid amide hydrolase inhibitor, binds to DJ-1 and forms a stable complex. URB597 treatment markedly reduced DJ-1 protein levels in SH-SY5Y cells, leading to decreased cell survival and impaired mitochondrial function under oxidative stress conditions. In addition, URB597-treated mice exhibited motor deficits and dopaminergic neuron loss, indicating that suppressing DJ-1 expression may adversely affect neuronal function. Gene expression and pathway enrichment analyses revealed that URB597 targets DJ-1 in the mouse striatum and regulates the expression of genes involved in protein acetylation. Collectively, these findings underscore the critical role of DJ-1 in protecting dopaminergic neurons from oxidative damage and uncover its potential implications in regulating protein acetylation.