Poster Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Transient neuroprotection by SRY upregulation in dopamine cells following injury in males (#303)

Vincent Harley 1 , Daniel P Czech 1 , Joohyung Lee 1 , Jeanne Correia 1 , Hannah Loke 1 , Eva K Möller 1
  1. MIMR-PHI Institute, Clayton, VIC, Australia

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) inhumanmaledopamineM17cells. SRY up-regulation occurred via the p-quinone pathway, associated with a 3.5-fold increase in expression of GADD45_, a DNA damage inducible factor gene and known SRY regulator. In turn, a signaling cascade involvingGADD45_/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.