Sex Hormones in Parkinson’s Disease

Abstract

The incidence of Parkinson’s disease (PD) is higher in the male population, and males are more likely to have earlier onset and more severe disease course, characterized by an akinetic-rigid phenotype with progression to freezing of gait, while females experience more benign symptoms such as tremor with progression to a postural instability and gait dysfunction phenotype. Striatal dopamine loss, neuronal cell death in the substantia nigra, and alpha-synuclein (α-syn) aggregations which can form Lewy bodies characterize PD pathology. Previous work to understand sex differences in PD has focused on how sex hormones may improve pathophysiology including cell viability, dopamine activity, neuroinflammation, and mitochondrial function. However, scarcely any research has been published regarding sex hormone interactions with α-syn proteostasis which underlies the formation of Lewy Bodies. I therefore used an in vitro dopaminergic neuronal model of PD in which both a wild type group and a group transfected to overexpress α-syn were treated with a range of concentrations of either estrogen or testosterone. The levels of oligomeric α-syn were significantly different in both wild-type and transfected cells depending on estrogen or testosterone treatment. Specifically, in the wild-type cells treated with estrogen, levels of oligomeric α-syn were lower compared to levels in cells treated with testosterone. However, in transfected cells, the levels of oligomeric α-syn were higher in estrogen treated versus testosterone treated cells. Neither estrogen nor testosterone significantly altered the levels of monomeric α-syn or α-syn phosphorylated at the 129-serine position in either wild type or transfected cells. Most interestingly, estrogen treatment significantly increased the ratio of oligomeric to monomeric α-syn in transfected cells. In conclusion, it may be the case that when monomeric α-syn accumulates as in PD, estrogen may facilitate turnover by autophagy of excess monomeric α-syn to form α-syn tetramers which play a role in healthy synaptic function. While this study reports altered oligomeric (~55kDa) α-syn levels in dopaminergic neurons following sex hormone treatments, it is yet to be known whether sex hormones directly or indirectly interact with α-syn to maintain proteostasis and inhibit fibrilization. Understanding the role sex hormones may play in α-syn accumulation and aggregation in PD is key for developing evidence-based therapeutics for disease subgroups.