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

Sophie Hu¹  Zhong Pei²  Jinsheng Zeng²  Fengjuan Su²  Simei Long²  Wenyuan Guo⁴  Christopher A. Ross⁵  Eng-King Tan⁶  Yixuan Zeng⁸ 

[1] Cumming School of Medicine, University of Calgary, Calgary, AB, Canada;Department 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, China;Department of Neurology, Singapore General Hospital, Singapore, Singapore;Department of Neurology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China;Division of Neurobiology, Department of Psychiatry–Departments of Neuroscience, Neurology, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United States;Duke-NUS Graduate Medical School, Singapore, Singapore;National Neuroscience Institute, Singapore, Singapore;Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China;

关键词: Parkinson’s disease;    G2019S LRRK2;    stress;    14-3-3;    daf-16;    Caenorhabditis elegans;   

DOI  :  10.3389/fnins.2018.00782

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown