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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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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.

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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

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).

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Correspondence to Tu-Hsueh Yeh or Hung-Li Wang.

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Chiu, CC., Lu, CS., Weng, YH. et al. 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. Mol Neurobiol 56, 3835–3853 (2019). https://doi.org/10.1007/s12035-018-1118-5

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