A novel splicing variant of DJ-1 in Parkinson's disease induces mitochondrial dysfunction
Namjoon Cho,
Jaegeon Joo,
Sunkyung Choi,
Bu-Gyeong Kang,
Andrew J. Lee,
So-Yeon Youn,
Su-Hyung Park,
Eun-Mi Kim,
Eliezer Masliah,
Yuji Ko,
Sun-Shin Cha,
Inkyung Jung,
Kee K. Kim
Affiliations
Namjoon Cho
Department of Biochemistry, Chungnam National University, Daejeon, 34134, Republic of Korea
Jaegeon Joo
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34134, Republic of Korea
Sunkyung Choi
Department of Biochemistry, Chungnam National University, Daejeon, 34134, Republic of Korea
Bu-Gyeong Kang
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, Republic of Korea
Andrew J. Lee
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34134, Republic of Korea
So-Yeon Youn
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, Republic of Korea
Su-Hyung Park
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34134, Republic of Korea
Eun-Mi Kim
Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, 34134, Republic of Korea
Eliezer Masliah
Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
Yuji Ko
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34134, Republic of Korea
Sun-Shin Cha
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, Republic of Korea; Corresponding author.
Inkyung Jung
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34134, Republic of Korea; Corresponding author.
Kee K. Kim
Department of Biochemistry, Chungnam National University, Daejeon, 34134, Republic of Korea; Corresponding author.
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.
