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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

  • 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
Article

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 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

Parkinson’s disease PARK14 (D331Y) PLA2G6 Knockin mice 

Notes

Acknowledgements

The authors are grateful to Microscopy Core Laboratory and Center for Advanced Molecular Imaging and Translation, Department of Nuclear Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. We thank Han Chiu and Chia-Chen Hsu for assistance and technical support. We would like to thank Chih-Wei Hu and Wen-Ai Wu of Transgenic Mouse Core Laboratory of Experimental Animal Center for help with ES cells microinjection.

Funding Information

This work was supported by the Ministry of Science and Technology, Taiwan (MOST 104-2314-B-182A-35-, MOST 105-2314-B-038-092-MY3 and MOST 105-2314-B-182A-013-MY3 to TH Yeh; MOST 105-2314-B-182A-003- and MOST 106-2314-B-182A-012-MY3 to CC Chiu; MOST104-2320-B-182-014-MY3 to HL Wang), Taipei Medical University (TMU106-AE1-B20 to TH Yeh), and the Chang Gung Medical Foundation (grants CMRPG3C1482, CMRPG3C0783, CMRPG3C1491, CMRPG3C1492, CMRPG3D0382, CRRPG3C0023, CRRPG3C0033 to TH Yeh.; CMRPG3F1821 to CC Chiu; CMRPD1B0332, CMRPD1C0623, CRRPD1C0013, CMRPD180433, and EMRPD1F0251 to HL Wang).

Compliance with Ethical Standards

Animal experiments were performed in accordance with protocols approved by Institutional Animal Care and Use Committee (IACUC) of Chang Gung University.

Conflict of Interest

The authors declare that they have no competing financial interests.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ching-Chi Chiu
    • 1
    • 2
    • 3
  • Chin-Song Lu
    • 1
    • 3
    • 4
    • 5
  • Yi-Hsin Weng
    • 1
    • 3
    • 4
    • 5
  • Ying-Ling Chen
    • 2
  • Ying-Zu Huang
    • 1
    • 3
    • 4
    • 5
    • 6
  • Rou-Shayn Chen
    • 1
    • 3
    • 4
    • 5
  • Yi-Chuan Cheng
    • 7
  • Yin-Cheng Huang
    • 5
    • 8
  • Yu-Chuan Liu
    • 9
  • Szu-Chia Lai
    • 1
    • 3
    • 4
    • 5
  • Kun-Jun Lin
    • 1
    • 10
  • Yan-Wei Lin
    • 1
    • 4
  • Yu-Jie Chen
    • 1
  • Chao-Lang Chen
    • 1
  • Tu-Hsueh Yeh
    • 11
    • 12
  • Hung-Li Wang
    • 1
    • 3
    • 4
    • 13
  1. 1.Neuroscience Research CenterChang Gung Memorial Hospital at LinkouTaoyuanTaiwan
  2. 2.Department of NursingChang Gung University of Science and TechnologyTaoyuanTaiwan
  3. 3.Healthy Aging Research CenterChang Gung University College of MedicineTaoyuanTaiwan
  4. 4.Division of Movement Disorders, Department of NeurologyChang Gung Memorial Hospital at LinkouTaoyuanTaiwan
  5. 5.College of MedicineChang Gung UniversityTaoyuanTaiwan
  6. 6.Institute of Cognitive NeuroscienceNational Central UniversityTaoyuanTaiwan
  7. 7.Graduate Institute of Biomedical SciencesChang Gung University College of MedicineTaoyuanTaiwan
  8. 8.Department of NeurosurgeryChang Gung Memorial Hospital at LinkouTaoyuanTaiwan
  9. 9.Division of Sports MedicineTaiwan Landseed HospitalTaoyuanTaiwan
  10. 10.Molecular Imaging CenterChang Gung Memorial Hospital at LinkouTaoyuanTaiwan
  11. 11.Department of NeurologyTaipei Medical University HospitalTaipei CityTaiwan
  12. 12.School of MedicineTaipei Medical UniversityTaipeiTaiwan
  13. 13.Department of Physiology and PharmacologyChang Gung University College of MedicineTaoyuanTaiwan

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