A novel splicing variant of DJ-1 in Parkinson's disease induces mitochondrial dysfunction.

Several studies have identified mutations in neuroprotective genes in a few cases of Parkinson's disease (PD); however, the role of alternative splicing changes in PD remains unelucidated. Based on the transcriptome analysis of substantia nigra (SN) tissues obtained from PD cases and age-matched healthy controls, we identified a novel alternative splicing variant of , lacking exon 6 ( ), frequently detected in the SN of patients with PD. We found that the exon 6 skipping of induces mitochondrial dysfunction and impaired antioxidant capability. According to an modeling study, the exon 6 skipping of DJ-1 disrupts the structural state suitable for the oxidation of the cysteine 106 residue that is a prerequisite for activating its neuroprotective roles. Our results suggest that change in alternative splicing may contribute to PD progression and provide an insight for studying PD etiology and its potential therapeutic targets.