Dexamethasone induces the expression of LRRK2 and α-synuclein, two genes that when mutated cause Parkinson's disease in an autosomal dominant manner.
LRRK2 (leucine-rich repeat kinase 2) has been identified as a gene corresponding to PARK8, an autosomal-dominant gene for familial Parkinson's disease (PD). LRRK2 pathogenic-specific mutants induce neurotoxicity and shorten neurites. To elucidate the mechanism underlying LRRK2 expression, we constructed the LRRK2-promoter-luciferase reporter and used it for promoter analysis. We found that the glucocorticoid receptor (GR) transactivated LRRK2 in a ligand-dependent manner. Using quantitative RT-PCR and Western analysis, we further showed that treatment with dexamethasone, a synthetic GR ligand, induced LRRK2 expression at both the transcriptional and translational levels, in dopaminergic MN9D cells. Dexamethasone treatment also increased expression of α α-synuclein, another PD causative gene, and enhanced transactivation of the α-synuclein promoter-luciferase reporter. In addition, dexamethasone treatment to MN9D cells weakly induced cytotoxicity based on an LDH assay. Because glucocorticoid hormones are secreted in response to stress, our data suggest that stress might be a related factor in the pathogenesis of PD.
Graduate program of Neuroscience, Inje University, Busan 614-735; InAm Neuroscience Research Center, Sanbon Hospital, Wonkwang University, Gunpo 435-040, Korea wseol@wmcsb.co.kr.
Ji-Min
JM
Park
Dong-Hwan
DH
Ho
Hye Jin
HJ
Yun
Hye-Jung
HJ
Kim
Chan Hong
CH
Lee
Sung Woo
SW
Park
Young Hoon
YH
Kim
Ilhong
I
Son
Wongi
W
Seol
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology* / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D051844:alpha-Synuclein; D003907:Dexamethasone; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases