G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans
Mutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson’s disease (PD). Oxidative stress plays a key role in the pathogenesis of PD. Mutations in LRRK2 have been shown to increase susceptibility to oxidative stress. To explore mechanisms underlying susceptibility to...
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2018.00782/full |
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| author | Simei Long Wenyuan Guo Sophie Hu Fengjuan Su Yixuan Zeng Jinsheng Zeng Eng-King Tan Eng-King Tan Eng-King Tan Christopher A. Ross Zhong Pei |
| author_facet | Simei Long Wenyuan Guo Sophie Hu Fengjuan Su Yixuan Zeng Jinsheng Zeng Eng-King Tan Eng-King Tan Eng-King Tan Christopher A. Ross Zhong Pei |
| author_sort | Simei Long |
| collection | DOAJ |
| description | Mutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson’s disease (PD). Oxidative stress plays a key role in the pathogenesis of PD. Mutations in LRRK2 have been shown to increase susceptibility to oxidative stress. To explore mechanisms underlying susceptibility to oxidative stress in LRRK2 mutants, we generated stable Caenorhabditis elegans (C. elegans) strains in which human LRRK2 proteins including wild type LRRK2 (WT), G2019S LRRK2 (G2019S), and G2019S-D1994A kinase-dead LRRK2 (KD) were expressed in all neurons. Human 14-3-3 β was injected into LRRK2 transgenic worms to allow co-expression of 14-3-3 β and LRRK2 proteins. We found that G2019S transgenic worms had increased sensitivity to stress (heat and juglone treatment) and impaired stress-induced nuclear translocation of DAF-16. In addition, G2019S inhibited ftt2 (a 14-3-3 gene homolog in C. elegans) knockdown-associated nuclear translocation of DAF-16. Comparably, overexpression of human 14-3-3 β could attenuate G2019S-associated toxicity in response to stress and rescued G2019S-mediated inhibition of sod-3 and dod-3 expression. Taken together, our study provides evidence suggesting that 14-3-3-associated inhibition of DAF-16 nuclear translocation could be a mechanism for G2019S LRRK2-induced oxidative stress and cellular toxicity. Our findings may give a hint that the potential of 14-3-3 proteins as neuroprotective targets in PD patients carrying LRRK2 mutations. |
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| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-16T16:12:29Z |
| publishDate | 2018-11-01 |
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| spelling | doaj.art-c4e7358847234d56aeaa0f87243cf4f12022-12-21T22:25:11ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2018-11-011210.3389/fnins.2018.00782409417G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegansSimei Long0Wenyuan Guo1Sophie Hu2Fengjuan Su3Yixuan Zeng4Jinsheng Zeng5Eng-King Tan6Eng-King Tan7Eng-King Tan8Christopher A. Ross9Zhong Pei10Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Neurology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, ChinaCumming School of Medicine, University of Calgary, Calgary, AB, CanadaDepartment of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaShenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, ChinaDepartment of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Neurology, Singapore General Hospital, Singapore, SingaporeNational Neuroscience Institute, Singapore, SingaporeDuke-NUS Graduate Medical School, Singapore, SingaporeDivision of Neurobiology, Department of Psychiatry–Departments of Neuroscience, Neurology, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaMutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson’s disease (PD). Oxidative stress plays a key role in the pathogenesis of PD. Mutations in LRRK2 have been shown to increase susceptibility to oxidative stress. To explore mechanisms underlying susceptibility to oxidative stress in LRRK2 mutants, we generated stable Caenorhabditis elegans (C. elegans) strains in which human LRRK2 proteins including wild type LRRK2 (WT), G2019S LRRK2 (G2019S), and G2019S-D1994A kinase-dead LRRK2 (KD) were expressed in all neurons. Human 14-3-3 β was injected into LRRK2 transgenic worms to allow co-expression of 14-3-3 β and LRRK2 proteins. We found that G2019S transgenic worms had increased sensitivity to stress (heat and juglone treatment) and impaired stress-induced nuclear translocation of DAF-16. In addition, G2019S inhibited ftt2 (a 14-3-3 gene homolog in C. elegans) knockdown-associated nuclear translocation of DAF-16. Comparably, overexpression of human 14-3-3 β could attenuate G2019S-associated toxicity in response to stress and rescued G2019S-mediated inhibition of sod-3 and dod-3 expression. Taken together, our study provides evidence suggesting that 14-3-3-associated inhibition of DAF-16 nuclear translocation could be a mechanism for G2019S LRRK2-induced oxidative stress and cellular toxicity. Our findings may give a hint that the potential of 14-3-3 proteins as neuroprotective targets in PD patients carrying LRRK2 mutations.https://www.frontiersin.org/article/10.3389/fnins.2018.00782/fullParkinson’s diseaseG2019S LRRK2stress14-3-3daf-16Caenorhabditis elegans |
| spellingShingle | Simei Long Wenyuan Guo Sophie Hu Fengjuan Su Yixuan Zeng Jinsheng Zeng Eng-King Tan Eng-King Tan Eng-King Tan Christopher A. Ross Zhong Pei G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans Frontiers in Neuroscience Parkinson’s disease G2019S LRRK2 stress 14-3-3 daf-16 Caenorhabditis elegans |
| title | G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans |
| title_full | G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans |
| title_fullStr | G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans |
| title_full_unstemmed | G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans |
| title_short | G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans |
| title_sort | g2019s lrrk2 increases stress susceptibility through inhibition of daf 16 nuclear translocation in a 14 3 3 associated manner in caenorhabditis elegans |
| topic | Parkinson’s disease G2019S LRRK2 stress 14-3-3 daf-16 Caenorhabditis elegans |
| url | https://www.frontiersin.org/article/10.3389/fnins.2018.00782/full |
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