Journal
ENDOCRINOLOGY
Volume 155, Issue 7, Pages 2602-2612Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2013-2158
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Funding
- Victorian Government's Operational Infrastructure Support Program, Australian NHMRC [334314, 546517, 1029401]
- Contributing to Australian Scholarship and Science foundation [SM/08/2053]
- Helen McPherson Smith Trust Project [5965]
- Australian National Health and Medical Research Council Postgraduate Award
- Prince Henry's Institute [13-20]
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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 GADD45 gamma, a DNA damage inducible factor gene and known SRY regulator. In turn, a signaling cascade involving GADD45 gamma/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.
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