DYSREGULATION OF SRY IN THE MALE BRAIN: A GENETIC BASIS FOR SEX BIAS IN NEUROLOGICAL DISORDERS? — ASN Events

DYSREGULATION OF SRY IN THE MALE BRAIN: A GENETIC BASIS FOR SEX BIAS IN NEUROLOGICAL DISORDERS? (#159)

Hannah Loke 1 2 , Paulo Pinares-Garcia 1 3 , Vincent Harley 1 2 3 , Joohyung Lee 1 2 3
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
  3. Department of Anatomy and Developmental Biology, Monash University , Clayton, Victoria, Australia

Sex differences in the dopamine (DA) pathway are likely to underlie male susceptibility to neurological disorders such as Parkinson’s disease (PD) and attention deficit hyperactivity disorder (ADHD). Aside from hormonal effects, recent evidence suggests that sex-chromosome genes may influence the sex differences in the healthy and diseased DA system. The Y-chromosome gene, SRY, is an ideal candidate to study, as it is found in various DA abundant brain regions. Our previous studies showed that SRY regulates DA biosynthesis and motor function in males. Thus, we propose that dysregulation in SRY expression could underlie male susceptibility to DA associated disorders such as PD and ADHD. To test this hypothesis, we investigated the regulation of SRY mRNA in in vitro and in vivo models of PD and ADHD. In the human male dopaminergic cell line, M17, SRY and GADD45γ (Growth arrest and DNA damage) mRNA expressions were significantly increased at 6 and 24h following 6-OHDA or rotenone treatment. In the 6-hydroxydopamine lesioned rat model, unilateral injection of 6-OHDA increased nigral SRY and GADD45γ mRNA expression from days 2 to 14 post-injection, which was associated with reductions in limb use and nigral TH expression in male rats. Injection of rotenone, also elevated SRY and GADD45γ mRNA expression at day 7 post-injection. In the spontaneously hypertensive rats (SHR), a well charaterised animal model of ADHD, male SHR showed significant hyperactivity in velocity and distance travelled as compared to the control male Wistar Kyoto rats (WKY) in the open field test. These behavioral differences were associated with significantly lower SRY mRNA expressions in the prefrontal cortex, hippocampus, hypothalamus and substantia nigra of male SHR compared to male WKY. In conclusion, we showed that SRY is upregulated in models of PD, and downregulated in a ADHD model, indicating that SRY dysregulation may underlie male susceptibility to these disorders. Thus, normalizing SRY expression may be a potential therapeutic strategy for treating DA-associated disorders such as PD and ADHD.

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