PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model

Ching Chi Chiu; Chin Song Lu; Yi Hsin Weng; Ying Ling Chen; Ying Zu Huang; Rou Shayn Chen; Yi Chuan Cheng; Yin Cheng Huang; Yu Chuan Liu; Szu Chia Lai; Kun Jun Lin; Yan Wei Lin; Yu Jie Chen; Chao Lang Chen; Tu Hsueh Yeh; Hung Li Wang

doi:10.1007/s12035-018-1118-5

PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model

Ching Chi Chiu, Chin Song Lu, Yi Hsin Weng, Ying Ling Chen, Ying Zu Huang, Rou Shayn Chen, Yi Chuan Cheng, Yin Cheng Huang, Yu Chuan Liu, Szu Chia Lai, Kun Jun Lin, Yan Wei Lin, Yu Jie Chen, Chao Lang Chen, Tu Hsueh Yeh, Hung Li Wang

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

34 Citations (Scopus)

Abstract

PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson’s disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6^D331Y/D331Y KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons. Six-or nine-month-old PLA2G6^D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons. Lewy body pathology was found in the SN of PLA2G6^D331Y/D331Y mice. Six-or nine-month-old PLA2G6^D331Y/D331Y KI mice exhibited early-onset parkinsonism phenotypes. Disrupted cristae of mitochondria were found in SNpc dopaminergic neurons of PLA2G6^D331Y/D331Y mice. PLA2G6^D331Y/D331Y mice displayed mitochondrial dysfunction and upregulated ROS production, which may lead to activation of apoptotic cascade. Upregulated protein levels of Grp78, IRE1, PERK, and CHOP, which are involved in activation of ER stress, were found in the SN of PLA2G6^D331Y/D331Y mice. Protein expression of mitophagic proteins, including parkin and BNIP3, was downregulated in the SN of PLA2G6^D331Y/D331Y mice, suggesting that (D331Y) PLA2G6 mutation causes mitophagy dysfunction. In the SN of PLA2G6^D331Y/D331Y mice, mRNA levels of eight genes that are involved in neuroprotection/neurogenesis were decreased, while mRNA levels of two genes that promote apoptotic death were increased. Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality.

Original language	English
Pages (from-to)	3835-3853
Number of pages	19
Journal	Molecular Neurobiology
Volume	56
Issue number	6
DOIs	https://doi.org/10.1007/s12035-018-1118-5
Publication status	Published - Jun 1 2019

Keywords

(D331Y) PLA2G6
Knockin mice
PARK14
Parkinson’s disease

ASJC Scopus subject areas

Neuroscience (miscellaneous)
Neurology
Cellular and Molecular Neuroscience

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Chiu, C. C., Lu, C. S., Weng, Y. H., Chen, Y. L., Huang, Y. Z., Chen, R. S., Cheng, Y. C., Huang, Y. C., Liu, Y. C., Lai, S. C., Lin, K. J., Lin, Y. W., Chen, Y. J., Chen, C. L., Yeh, T. H., & Wang, H. L. (2019). PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model. Molecular Neurobiology, 56(6), 3835-3853. https://doi.org/10.1007/s12035-018-1118-5

PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model. / Chiu, Ching Chi; Lu, Chin Song; Weng, Yi Hsin et al.
In: Molecular Neurobiology, Vol. 56, No. 6, 01.06.2019, p. 3835-3853.

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

Chiu, CC, Lu, CS, Weng, YH, Chen, YL, Huang, YZ, Chen, RS, Cheng, YC, Huang, YC, Liu, YC, Lai, SC, Lin, KJ, Lin, YW, Chen, YJ, Chen, CL, Yeh, TH & Wang, HL 2019, 'PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model', Molecular Neurobiology, vol. 56, no. 6, pp. 3835-3853. https://doi.org/10.1007/s12035-018-1118-5

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title = "PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model",

abstract = "PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson{\textquoteright}s disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6D331Y/D331Y KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons. Lewy body pathology was found in the SN of PLA2G6D331Y/D331Y mice. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice exhibited early-onset parkinsonism phenotypes. Disrupted cristae of mitochondria were found in SNpc dopaminergic neurons of PLA2G6D331Y/D331Y mice. PLA2G6D331Y/D331Y mice displayed mitochondrial dysfunction and upregulated ROS production, which may lead to activation of apoptotic cascade. Upregulated protein levels of Grp78, IRE1, PERK, and CHOP, which are involved in activation of ER stress, were found in the SN of PLA2G6D331Y/D331Y mice. Protein expression of mitophagic proteins, including parkin and BNIP3, was downregulated in the SN of PLA2G6D331Y/D331Y mice, suggesting that (D331Y) PLA2G6 mutation causes mitophagy dysfunction. In the SN of PLA2G6D331Y/D331Y mice, mRNA levels of eight genes that are involved in neuroprotection/neurogenesis were decreased, while mRNA levels of two genes that promote apoptotic death were increased. Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality.",

keywords = "(D331Y) PLA2G6, Knockin mice, PARK14, Parkinson{\textquoteright}s disease",

author = "Chiu, {Ching Chi} and Lu, {Chin Song} and Weng, {Yi Hsin} and Chen, {Ying Ling} and Huang, {Ying Zu} and Chen, {Rou Shayn} and Cheng, {Yi Chuan} and Huang, {Yin Cheng} and Liu, {Yu Chuan} and Lai, {Szu Chia} and Lin, {Kun Jun} and Lin, {Yan Wei} and Chen, {Yu Jie} and Chen, {Chao Lang} and Yeh, {Tu Hsueh} and Wang, {Hung Li}",

year = "2019",

month = jun,

day = "1",

doi = "10.1007/s12035-018-1118-5",

language = "English",

volume = "56",

pages = "3835--3853",

journal = "Molecular Neurobiology",

issn = "0893-7648",

publisher = "Humana Press",

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TY - JOUR

T1 - PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model

AU - Chiu, Ching Chi

AU - Lu, Chin Song

AU - Weng, Yi Hsin

AU - Chen, Ying Ling

AU - Huang, Ying Zu

AU - Chen, Rou Shayn

AU - Cheng, Yi Chuan

AU - Huang, Yin Cheng

AU - Liu, Yu Chuan

AU - Lai, Szu Chia

AU - Lin, Kun Jun

AU - Lin, Yan Wei

AU - Chen, Yu Jie

AU - Chen, Chao Lang

AU - Yeh, Tu Hsueh

AU - Wang, Hung Li

PY - 2019/6/1

Y1 - 2019/6/1

N2 - PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson’s disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6D331Y/D331Y KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons. Lewy body pathology was found in the SN of PLA2G6D331Y/D331Y mice. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice exhibited early-onset parkinsonism phenotypes. Disrupted cristae of mitochondria were found in SNpc dopaminergic neurons of PLA2G6D331Y/D331Y mice. PLA2G6D331Y/D331Y mice displayed mitochondrial dysfunction and upregulated ROS production, which may lead to activation of apoptotic cascade. Upregulated protein levels of Grp78, IRE1, PERK, and CHOP, which are involved in activation of ER stress, were found in the SN of PLA2G6D331Y/D331Y mice. Protein expression of mitophagic proteins, including parkin and BNIP3, was downregulated in the SN of PLA2G6D331Y/D331Y mice, suggesting that (D331Y) PLA2G6 mutation causes mitophagy dysfunction. In the SN of PLA2G6D331Y/D331Y mice, mRNA levels of eight genes that are involved in neuroprotection/neurogenesis were decreased, while mRNA levels of two genes that promote apoptotic death were increased. Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality.

AB - PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson’s disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6D331Y/D331Y KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons. Lewy body pathology was found in the SN of PLA2G6D331Y/D331Y mice. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice exhibited early-onset parkinsonism phenotypes. Disrupted cristae of mitochondria were found in SNpc dopaminergic neurons of PLA2G6D331Y/D331Y mice. PLA2G6D331Y/D331Y mice displayed mitochondrial dysfunction and upregulated ROS production, which may lead to activation of apoptotic cascade. Upregulated protein levels of Grp78, IRE1, PERK, and CHOP, which are involved in activation of ER stress, were found in the SN of PLA2G6D331Y/D331Y mice. Protein expression of mitophagic proteins, including parkin and BNIP3, was downregulated in the SN of PLA2G6D331Y/D331Y mice, suggesting that (D331Y) PLA2G6 mutation causes mitophagy dysfunction. In the SN of PLA2G6D331Y/D331Y mice, mRNA levels of eight genes that are involved in neuroprotection/neurogenesis were decreased, while mRNA levels of two genes that promote apoptotic death were increased. Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality.

KW - (D331Y) PLA2G6

KW - Knockin mice

KW - PARK14

KW - Parkinson’s disease

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SN - 0893-7648

VL - 56

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JO - Molecular Neurobiology

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PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model

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