A novel splicing variant of DJ-1 in Parkinson's disease induces mitochondrial dysfunction
Namjoon Cho, Jaegeon Joo, Sunkyung Choi, Bu-Gyeong Kang, Andrew Lee, So-Yeon Youn, Su‐Hyung Park, Eun Mi Kim, Eliezer Masliah, Yuji Ko, Sun‐Shin Cha, Inkyung Jung, Kee K. Kim
Abstract
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 DJ-1, lacking exon 6 (DJ-1ΔE6), frequently detected in the SN of patients with PD. We found that the exon 6 skipping of DJ-1 induces mitochondrial dysfunction and impaired antioxidant capability. According to an in silico 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 DJ-1 alternative splicing may contribute to PD progression and provide an insight for studying PD etiology and its potential therapeutic targets.