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PMID:23628791

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Citation

Roth, JA and Eichhorn, M (2013) Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity. Neurotoxicology 37:100-7

Abstract

The extra-pyramidal symptoms associated with manganism often overlap with that seen in Parkinsonism suggesting a common link between the two disorders. Since wide deviations are observed in susceptibility and characteristics of the symptoms observed in manganism, these differences may be due to underlying genetic variability. Genes linked to early onset of Parkinsonism which includes ATP13A2 and parkin have already been suggested to promote development of Mn toxicity. Of the other Parkinson-linked genes, mutations in LRRK2, an autosomal dominant gene, represent another likely candidate involved in the development of manganism. In this paper the effect of shRNA LRRK2 knock-down on Mn toxicity was examined in control and DAT transfected HEK293 cells. Results demonstrate that LRRK2 down-regulation potentiates Mn toxicity in both control and DAT-transfected cell as well as potentiates DA toxicity. Combined treatment of Mn and DA further augments cell toxicity, ROS production and JNK phosphorylation in LRRK2 deficient cells compared to controls. Consistent with studies demonstrating that LRRK2 plays a role in the phosphorylation of p38, our results similarly demonstrate a decrease in p38 activation in LRRK2 knock-down cells. Our findings suggest that null mutations in LRRK2 which cause Parkinsonism potentiate Mn toxicity and increase susceptibility to develop manganism.

Links

PubMed PMC3698986 Online version:10.1016/j.neuro.2013.04.008

Keywords

Cell Survival/drug effects; Dopamine/toxicity; Dopamine Plasma Membrane Transport Proteins/genetics; Dopamine Plasma Membrane Transport Proteins/metabolism; Dose-Response Relationship, Drug; Down-Regulation; HEK293 Cells; Humans; JNK Mitogen-Activated Protein Kinases/metabolism; Manganese/toxicity; Oxidative Stress/drug effects; Phosphorylation; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA Interference; Reactive Oxygen Species/metabolism; Transfection; p38 Mitogen-Activated Protein Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PRKN

involved_in

GO:0071287: cellular response to manganese ion

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:0071287: cellular response to manganese ion

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PRKN2

involved_in

GO:0071287: cellular response to manganese ion

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LRRK2

involved_in

GO:0071287: cellular response to manganese ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LRRK2

involved_in

GO:1903351: cellular response to dopamine

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LRRK2

involved_in

GO:0043406: positive regulation of MAP kinase activity

ECO:0000305: curator inference used in manual assertion

GO:0006468

P

Seeded From UniProt

complete

HUMAN:LRRK2

involved_in

GO:0006468: protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:0071287: cellular response to manganese ion

ECO:0000304: author statement supported by traceable reference used in manual assertion


P

Seeded From UniProt

complete

Notes

See also

References

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