Transient neuroprotection by SRY upregulation in dopamine cells following injury in males.
Emerging evidence suggest sex-specific regulation of dopamine neurons may underlie susceptibility of males to disorders such as Parkinson's disease (PD). In healthy male dopamine neurons, the Y-chromosome gene product, the sex-determining region on the Y chromosome (SRY) modulates dopamine biosynthesis and motor function. We investigated the regulation and function of SRY in a model of dopamine cell injury. Treatment with the dopaminergic toxin, 6-hydroxydopamine (6-OHDA), significantly elevated SRY mRNA expression (9-fold) in human male dopamine M17 cells. SRY up-regulation occurred via the p-quinone pathway, associated with a 3.5-fold increase in expression of GADD45γ, a DNA damage inducible factor gene and known SRY regulator. In turn, a signaling cascade involving GADD45γ/p38-MAPK/GATA activated the SRY promoter. Knockdown of SRY mRNA in 6-OHDA-treated M17 cells was deleterious, increasing levels of reactive oxygen species (ROS), pro-apoptotic marker PUMA mRNA, and cell injury (+25%, +32% and +34%, respectively). Conversely, ectopic over-expression of SRY in 6-OHDA-treated female SH-SY5Y cells was protective, decreasing ROS, PUMA, and cell injury (-40%, -46%, and -30%, respectively). However, the 6-OHDA-induced increase in SRY expression was diminished with higher concentrations of toxins or with chronic exposure to 6-OHDA. We conclude that SRY upregulation after dopamine cell injury is initially a protective response in males, but diminishes with gradual loss in dopamine cells. We speculate that dysregulation of SRY may contribute the susceptibility of males to PD.
Brain and Gender Laboratory (D.P.C., J.L., J.C., H.L., E.K.M., V.R.H.), MIMR-PHI (formerly Prince Henry's Institute of Medical Research), Department of Biochemistry and Molecular Biology (D.P.C., V.R.H.), and Department of Anatomy and Developmental Biology (J.L., V.R.H), Monash University, Melbourne, 3168, Victoria, Australia.
Daniel P
DP
Czech
Joohyung
J
Lee
Jeanne
J
Correia
Hannah
H
Loke
Eva K
EK
Möller
Vincent R
VR
Harley
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D016227:Benzoquinones / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D050980:GATA Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051876:Sex-Determining Region Y Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D004298:Dopamine; D050980:GATA Transcription Factors; D006861:Hydrogen Peroxide; D047908:Intracellular Signaling Peptides and Proteins; D016627:Oxidopamine; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D051876:Sex-Determining Region Y Protein; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins; C438378:BBC3 protein, human; C004532:quinone