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The Role of Human SRY in Healthy and Diseased Male Dopamine Neurons
thesisposted on 21.02.2017, 02:55 by Czech, Daniel Peter
Notwithstanding the many similarities between men and women, there are remarkable biological differences between the male and female brain. Complex brain sex differences are found in neuroanatomy, neurochemistry and in behaviour. It is thought that biological sex differences can manifest in neurological conditions, leading to sex bias in diseases of the brain. Common amongst reports of sex differences in the brain are those involving dopamine pathways. Several disorders related to the dysfunction of dopamine pathways are thought to be found more often in men than women, including Parkinson’s disease (PD). Despite much investigation, debate still surrounds the origins of sex differences in dopamine pathways, particularly the level of contribution attributed to hormonal versus genetic factors. Evidence suggests that the action of sex hormones does not solely explain sex differences in dopamine systems. Certainly sex chromosome genes could be in-part responsible for sex differences in dopamine pathways. Sex determining region on the Y chromosome (SRY) is the gene responsible for differentiating the bipotential gonad into a testis during embryonic development. However, the unexpected presence of SRY in dopamine neurons of the rodent substantia nigra pars compacta (SNc) and its novel function in the control of voluntary movement in male rodents suggests it plays a role in the regulation of dopamine transmission and dopamine-related disorders with sex bias such as PD. This thesis investigates the expression, regulation and function of human SRY in healthy and diseased male dopamine neurons. In human male SNc dopamine neurons, SRY localizes with tyrosine hydroxylase (TH). SRY was also detected in TH-positive neurons of the male VTA and glutamate decarboxylase-positive neurons of the male SNr. In human male dopamine M17 cells, SRY regulates dopamine levels via transcriptional regulation of components essential for catecholamine biosynthesis, metabolism and signalling. The presence of SRY in dopamine neurons of the male SNc, a region preferentially damaged in PD, prompted the investigation of SRY regulation and function in the 6-hydroxydopamine (6-OHDA) PD cell model. In injured male dopamine cells, low doses of/acute PD toxin 6-OHDA strongly up-regulates SRY expression. Increased SRY expression is transient and diminishes with increasing concentrations of 6-OHDA toxin or chronic injury. Preliminary investigation in end-stage PD suggests that SRY is diminished in male SNc dopamine neurons, which could suggest involvement in the increased male-susceptibility of the disease. The mechanism of transient SRY up-regulation in male dopamine cells is found to be similar to that in gonadal cells, where the DNA damage response factor GADD45γ induces p38-MAPK/GATA to transcriptionally activate the gene. SRY is demonstrated to be protective against the generation of reactive oxygen species and death in dopamine cells. It is speculated here that up-regulation of SRY following injury may represent an acute protective response by the gene. SRY-responsive, neuroprotective genes were identified using an SRY-overexpression microarray approach. Several candidate SRY-responsive genes involved in neuroprotection were identified. Combined, these results suggest that in the human male dopamine neuron SRY may play a role as a positive regulator of dopamine biosynthesis and that in injured neurons SRY may have an acute neuroprotective function, which is lost with diminished SRY expression during chronic injury. Elucidating the role of SRY in healthy dopamine cells and the neuroprotective function of SRY in injured dopamine cells could lead to the development of novel pharmacological agents which improve outcomes for neurological disease such as PD.