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This is your chance to make annotations OR challenge other team's annotations. You may also DEFEND or suggest improvements to your own annotations IF they have been challenged. Please note, although we ENCOURAGE challenges, an excess of identical challenges that do not appear to be applicable to the annotation or well thought out will be considered spam and ignored.

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PMID:21857923

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Citation

Yuan, Y, Cao, P, Smith, MA, Kramp, K, Huang, Y, Hisamoto, N, Matsumoto, K, Hatzoglou, M, Jin, H and Feng, Z (2011) Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans. PLoS ONE 6:e22354

Abstract

Mutation of leucine-rich repeat kinase 2 (LRRK2) is the leading genetic cause of Parkinson's Disease (PD), manifested as age-dependent dopaminergic neurodegeneration, but the underlying molecular mechanisms remain unclear. Multiple roles of LRRK2 may contribute to dopaminergic neurodegeneration. Endoplasmic reticulum (ER) stress has also been linked to PD pathogenesis, but its interactive mechanism with PD genetic factors is largely unknown. Here, we used C. elegans, human neuroblastoma cells and murine cortical neurons to determine the role of LRRK2 in maintaining dopaminergic neuron viability. We found that LRRK2 acts to protect neuroblastoma cells and C. elegans dopaminergic neurons from the toxicity of 6-hydroxydopamine and/or human α-synuclein, possibly through the p38 pathway, by supporting upregulation of GRP78, a key cell survival molecule during ER stress. A pathogenic LRRK2 mutant (G2019S), however, caused chronic p38 activation that led to death of murine neurons and age-related dopaminergic-specific neurodegeneration in nematodes. These observations establish a critical functional link between LRRK2 and ER stress.

Links

PubMed PMC3153934 Online version:10.1371/journal.pone.0022354

Keywords

Animals; Animals, Genetically Modified; Blotting, Western; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; Cell Line, Tumor; Cells, Cultured; Dopaminergic Neurons/metabolism; Dopaminergic Neurons/pathology; Endoplasmic Reticulum Stress; Green Fluorescent Proteins/genetics; Green Fluorescent Proteins/metabolism; HEK293 Cells; Heat-Shock Proteins/genetics; Heat-Shock Proteins/metabolism; Humans; Mice; Microscopy, Confocal; Mitogen-Activated Protein Kinases/metabolism; Mutation; Nerve Degeneration/chemically induced; Oxidopamine; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA Interference; Signal Transduction; p38 Mitogen-Activated Protein Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status

HUMAN:LRRK2

GO:0000187

activation of MAPK activity

IMP: Inferred from Mutant Phenotype

P

Seeded From UniProt

complete

HUMAN:LRRK2

GO:0034599

cellular response to oxidative stress

IMP: Inferred from Mutant Phenotype

P

Seeded From UniProt

complete

HUMAN:LRRK2

GO:1901215

negative regulation of neuron death

IGI: Inferred from Genetic Interaction

UniProtKB:Q9TZM3

P

Seeded From UniProt

complete

HUMAN:LRRK2

GO:1902236

negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway

IMP: Inferred from Mutant Phenotype

P

Seeded From UniProt

complete

CAEEL:PMK1

GO:1901215

negative regulation of neuron death

IMP: Inferred from Mutant Phenotype

P

Seeded From UniProt

complete

Notes

See also

References

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