PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway

Chiu, Ching-Chi; Yeh, Tu Hsueh; Lu, Chin Song; Huang, Yin; Yi, Cheng; Huang, Ying Zu; Weng, Yueh-Hsuan; Liu, Yu Chuan; Lai, Shen‐Hao; Chen, Ying Ling; Chen, Yu Jie; Chen, Chao Lang; Chen, Hsin Yi; Yan, Lin; Wang, Hung Li

doi:10.18632/oncotarget.20893

Cited by 41 publications

(22 citation statements)

References 64 publications

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“…Several animal models have demonstrated that expression of iPLA2β prevents the loss of mitochondrial membrane potential and attenuates the cytochrome c release, the decrease of ROS and mitochondrial lipid peroxidation in response to stress-induced apoptosis, protecting mitochondria. The apoptotic cascade, ROS and lipid peroxides are enough to originate a neuroinflammation response, which may potentiate PLAN pathogenesis [ 106 , 119 , 120 , 121 ].…”

Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

et al. 2020

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The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

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Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

et al. 2020

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“…Azoramide reduces the increase in ROS and ameliorates the decline in mitochondrial membrane potential in PLA2G6 D331Y/D331Y midbrain DA neurons Oxidative stress causes the release of cytochrome c from mitochondria, which activates the apoptotic pathway [21][22][23][24][25] . Intracellular ROS in DA neurons was measured with the fluorescent probe CellROX® Green Reagent.…”

Section: Azoramide Attenuates Loss Of Pla2g6 D331y/d331y Ipscderived mentioning

confidence: 99%

Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling

Chong

Zeng

et al. 2020

Cell Death Dis

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The endoplasmic reticulum (ER)-stress-induced cascade events are implicated in Parkinson's disease (PD). The discovery of drug candidates to protect dopaminergic (DA) neurons from ER-stress-induced oxidative damage is important to resolve the pathological aspects of PD and modify its progress. In this study, we found that a recently identified unfolded protein response (UPR) modulator, azoramide, showed protective effects on patient induced pluripotent stem cells-derived midbrain DA neurons with the homozygous phospholipase A2 group 6 (PLA2G6) D331Y mutant. A series of PD-related cascade events such as ER stress, abnormal calcium homeostasis, mitochondrial dysfunction, increase of reactive oxygen species, and apoptosis were observed in PLA2G6 D331Y mutant DA neurons, whereas azoramide significantly protected PLA2G6 D331Y mutant DA neurons against these events. The beneficial effects of azoramide were abolished by treatment with a cAMP-response element binding protein (CREB) inhibitor. Our results suggest that azoramide is a potential neuroprotectant against DA neuron damage via restoring ER function and the CREB signaling.

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“…The phospholipase A2 activity of PLA2G6 was measured using a modified commercial kit that was originally designed for cPLA2 (Cayman Chemicals), as described previously (19). Briefly, the total protein was extracted and incubated in a modified calcium-free buffer (4 mM EGTA, 160 mM HEPES, pH 7.4, 300 mM NaCl, 8 mM Triton X-100, 60% glycerol, and 2 mg/mL BSA) with arachidonoyl thiophosphatidylcholine (ARA-PC) and the synthetic substrate of phospholipase for 2 h at room temperature.…”

Section: Phospholipase Activitymentioning

confidence: 99%

Overexpressing PLA2G6 mutations cause symptoms of young–onset dystonia–parkinsonism type 14 and reduction in DHA levels in zebrafish model

Yeh

Liu

Cheng

et al. 2020

Preprint

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Background: Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, which is currently incurable. Mutations in many genes have been demonstrated to be the primary risk factors associated with the familial or idiopathic PD; however, the mechanisms underlying these genetic mutations resulting in parkinsonism remains unclear. Phospholipase A2 group VI (PLA2G6) has been shown to regulate lipid metabolism and homeostasis in the nervous system. Previous studies have shown that point mutations in PLA2G6 might be the risk factors associated with the young–onset of dystonia–parkinsonism type 14 (PARK14). However, limited information is available regarding its pathogenic role and the mechanism underlying its function. Methods: To study the role of PLA2G6 mutations in zebrafish PARK14 models, we injected different mutation constructs of human PLA2G6 genes and zebrafish pla2g6 deletion constructs in the zebrafish larvae. We analyzed the locomotion behavior, performed immunohistochemistry to examine the formation of dopaminergic neurons, and identified the defective metabolites affected by PLA2G6 mutations through metabolomics analysis. Results: Injection of human PLA2G6 mutations and zebrafish pla2g6 deletion constructs induced symptoms such as motility defects and reduced number of dopaminergic neurons, and these symptoms resembled those observed in PARK14. These phenotypes could be rescued by treatment with L-dopa. Furthermore, the injection of two PLA2G6 mutation constructs, D331Y and T572I, led to a decrease in the phospholipase activity of PLA2G6 and its lipid metabolites, indicating that these two mutations are the loss-of-function mutations. We further performed metabolomics analysis to identify which lipids are majorly affected by the overexpression of PLA2G6 and PLA2G6 mutants. We found that injecting D331Y or T572I mutation constructs led to higher phospholipid and lower DHA levels. Conclusions: D331Y and T572I injections in zebrafish were sufficient to create a PD phenotypes. In addition, D331Y and T572I are loss of function mutations and cause defective phospholipase activity and reduced the level of DHA. These results have helped us elucidate the role of PLA2G6 mutations in PARK14 and further led to a deeper understanding of the molecular mechanisms underlying PD. The results of this study may also facilitate the development of therapeutic strategies for PD.

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PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway

Cited by 41 publications

References 64 publications

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling

Overexpressing PLA2G6 mutations cause symptoms of young–onset dystonia–parkinsonism type 14 and reduction in DHA levels in zebrafish model

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