G2019S LRRK2 increases stress susceptibility through inhibition of DAF-16 nuclear translocation in a 14-3-3 associated-manner in caenorhabditis elegans

Simei Long, Wenyuan Guo, Sophie Hu, Fengjuan Su, Yixuan Zeng, Jinsheng Zeng, Eng King Tan, Christopher A Ross, Zhong Pei

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number782
JournalFrontiers in Neuroscience
Volume12
Issue numberNOV
DOIs
StatePublished - Nov 7 2018

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Caenorhabditis elegans
Leucine
Phosphotransferases
Oxidative Stress
Parkinson Disease
Mutation
14-3-3 Proteins
Protein Kinases
Hot Temperature
Neurons

Keywords

  • 14-3-3
  • Caenorhabditis elegans
  • Daf-16
  • G2019S LRRK2
  • Parkinson’s disease
  • Stress

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

G2019S LRRK2 increases stress susceptibility through inhibition of DAF-16 nuclear translocation in a 14-3-3 associated-manner in caenorhabditis elegans. / Long, Simei; Guo, Wenyuan; Hu, Sophie; Su, Fengjuan; Zeng, Yixuan; Zeng, Jinsheng; Tan, Eng King; Ross, Christopher A; Pei, Zhong.

In: Frontiers in Neuroscience, Vol. 12, No. NOV, 782, 07.11.2018.

Research output: Contribution to journalArticle

Long, Simei ; Guo, Wenyuan ; Hu, Sophie ; Su, Fengjuan ; Zeng, Yixuan ; Zeng, Jinsheng ; Tan, Eng King ; Ross, Christopher A ; Pei, Zhong. / G2019S LRRK2 increases stress susceptibility through inhibition of DAF-16 nuclear translocation in a 14-3-3 associated-manner in caenorhabditis elegans. In: Frontiers in Neuroscience. 2018 ; Vol. 12, No. NOV.
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abstract = "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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AU - Long, Simei

AU - Guo, Wenyuan

AU - Hu, Sophie

AU - Su, Fengjuan

AU - Zeng, Yixuan

AU - Zeng, Jinsheng

AU - Tan, Eng King

AU - Ross, Christopher A

AU - Pei, Zhong

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AB - 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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