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

被引：8

作者：

Cho, Namjoon ^{[1
]}

Joo, Jaegeon ^{[2
]}

Choi, Sunkyung ^{[1
]}

Kang, Bu-Gyeong ^{[3
]}

Lee, Andrew J. ^{[2
]}

Youn, So-Yeon ^{[3
]}

Park, Su-Hyung ^{[4
]}

Kim, Eun-Mi ^{[5
]}

Masliah, Eliezer ^{[6
]}

Ko, Yuji

Cha, Sun-Shin ^{[3
]}

Jung, Inkyung ^{[2
]}

Kim, Kee K. ^{[1
]}

机构：

[1] Chungnam Natl Univ, Dept Biochem, Daejeon 34134, South Korea

[2] Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, Daejeon 34134, South Korea

[3] Ewha Womans Univ, Dept Chem & Nanosci, Seoul 03760, South Korea

[4] Korea Adv Inst Sci & Technol KAIST, Biomed Sci & Engn Interdisciplinary Program, Daejeon 34134, South Korea

[5] Korea Inst Toxicol, Dept Predict Toxicol, Daejeon 34134, South Korea

[6] NIA, Mol Neuropathol Sect, Lab Neurogenet, NIH, Bethesda, MD 20892 USA

来源：

HELIYON | 2023年 / 9卷 / 03期

基金：

新加坡国家研究基金会;

关键词：

DJ-1; PARK7; Parkinson?s disease; Alternative splicing; Mitochondria; CYSTEINE-SULFINIC ACID; TYROSINE-HYDROXYLASE; OXIDATIVE STRESS; CELL-DEATH; PROTEIN; BIOENERGETICS; TRANSCRIPTOME; STRINGTIE; SEQUENCE; MODEL;

D O I：

10.1016/j.heliyon.2023.e14039

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 agematched healthy controls, we identified a novel alternative splicing variant of DJ-1, lacking exon 6 (DJ-1 Delta E6), 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.

引用

页数：12

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