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

doi:10.1016/j.heliyon.2023.e14039

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

Department of Chemistry & Nanoscience

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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-1^ΔE6), 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.

Original language	English
Article number	e14039
Journal	Heliyon
Volume	9
Issue number	3
DOIs	https://doi.org/10.1016/j.heliyon.2023.e14039
State	Published - Mar 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

Alternative splicing
DJ-1
Mitochondria
PARK7
Parkinson's disease

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10.1016/j.heliyon.2023.e14039

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title = "A novel splicing variant of DJ-1 in Parkinson's disease induces mitochondrial dysfunction",

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.",

keywords = "Alternative splicing, DJ-1, Mitochondria, PARK7, Parkinson's disease",

author = "Namjoon Cho and Jaegeon Joo and Sunkyung Choi and Kang, {Bu Gyeong} and Lee, {Andrew J.} and Youn, {So Yeon} and Park, {Su Hyung} and Kim, {Eun Mi} and Eliezer Masliah and Yuji Ko and Cha, {Sun Shin} and Inkyung Jung and Kim, {Kee K.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = mar,

doi = "10.1016/j.heliyon.2023.e14039",

language = "English",

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T1 - A novel splicing variant of DJ-1 in Parkinson's disease induces mitochondrial dysfunction

AU - Cho, Namjoon

AU - Joo, Jaegeon

AU - Choi, Sunkyung

AU - Kang, Bu Gyeong

AU - Lee, Andrew J.

AU - Youn, So Yeon

AU - Park, Su Hyung

AU - Kim, Eun Mi

AU - Masliah, Eliezer

AU - Ko, Yuji

AU - Cha, Sun Shin

AU - Jung, Inkyung

AU - Kim, Kee K.

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

KW - Alternative splicing

KW - DJ-1

KW - Mitochondria

KW - PARK7

KW - Parkinson's disease

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DO - 10.1016/j.heliyon.2023.e14039

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SN - 2405-8440

VL - 9

JO - Heliyon

JF - Heliyon

IS - 3

M1 - e14039

ER -

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

Abstract

Bibliographical note

Keywords

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