Emerging evidence suggest a sex-specific regulation of dopamine neurons, which may underlie susceptibility of males to disorders such as Parkinson s disease (PD). In healthy male dopamine neurons, the Y-chromosome gene product, 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 GADD45gamma, a DNA damage inducible factor and known SRY regulator. In turn, a signalling cascade involving GADD45gamma/p38-MAPK/GATA activated the SRY promoter. Knockdown of SRY mRNA in 6-OHDA-treated M17 cells was deleterious, with increased 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, 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 up-regulation following dopamine cell injury is initially a protective response in males, but diminishes with gradual loss in dopamine cells. Hence, dysregulation of SRY may underlie susceptibility of males to PD.