@article{5e262cd078864ec19667b164bd3f3e37,
title = "G2019S LRRK2 increases stress susceptibility through inhibition of DAF-16 nuclear translocation in a 14-3-3 associated-manner in caenorhabditis elegans",
abstract = "Mutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson{\textquoteright}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.",
keywords = "14-3-3, Caenorhabditis elegans, Daf-16, G2019S LRRK2, Parkinson{\textquoteright}s disease, Stress",
author = "Simei Long and Wenyuan Guo and Sophie Hu and Fengjuan Su and Yixuan Zeng and Jinsheng Zeng and Tan, {Eng King} and Ross, {Christopher A.} and Zhong Pei",
note = "Funding Information: The study was supported by the grants from: the National Natural Science Foundation of China (Grant Nos. 81671102 and 81371255); The National Key Research and Development Program of China, Stem Cell and Translational Research (Grant No. 2017YFA0105104); Guangdong provincial science and technology plan project (Grant Nos. 2016B030230002 and 2017A040406007); Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases (Grant No. 2017B030314103); The Southern China International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases (2015B050501003); and Guangdong Provincial Engineering Center for Major Neurological Disease Treatment. Funding Information: We are grateful to Dr. King L. Chow, Hong Kong University of Science and Technology for assistance in helping us learn techniques in developing stable C. elegans lines. We are also thankful to Dr. Bin Hu for providing input on the models, our results, and final editing. This study was supported by the grants from Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). We also thank LiwenBianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript. Publisher Copyright: Copyright {\textcopyright} 2018 Long, Guo, Hu, Su, Zeng, Zeng, Tan, Ross and Pei.",
year = "2018",
month = nov,
day = "7",
doi = "10.3389/fnins.2018.00782",
language = "English (US)",
volume = "12",
journal = "Frontiers in Neuroscience",
issn = "1662-4548",
publisher = "Frontiers Research Foundation",
number = "NOV",
}