Sex differences in Parkinson's disease

Abstract

Parkinson's disease (PD) displays a greater prevalence and earlier age at onset in men. This review addresses the concept that sex differences in PD are determined, largely, by biological sex differences in the NSDA system which, in turn, arise from hormonal, genetic and environmental influences. Current therapies for PD rely on dopamine replacement strategies to treat symptoms, and there is an urgent, unmet need for disease modifying agents. As a significant degree of neuroprotection against the early stages of clinical or experimental PD is seen, respectively, in human and rodent females compared with males, a better understanding of brain sex dimorphisms in the intact and injured NSDA system will shed light on mechanisms which have the potential to delay, or even halt, the progression of PD. Available evidence suggests that sex-specific, hormone-based therapeutic agents hold particular promise for developing treatments with optimal efficacy in men and women.

Keywords: Neuroprotection; Nigrostriatal dopaminergic pathways; Parkinson’s disease; Sex differences; Sex hormones.

Fig. 1

Hormonal influences on 6-OHDA-induced lesions in the nigrostriatal dopaminergic pathway. Male and female rats underwent bilateral gonadectomy (GDX) or sham operation (controls). While still under anaesthesia, animals received a subcutaneous implant of slow release pellets containing estradiol (GDX + E2 to replicate proestrous levels), 5α-dihydrotestosterone (GDX + DHT to replicate physiological androgen levels) or a placebo pellet (GDX group). One week later all animals received a unilateral injection of 1 μg 6-OHDA into the left medial forebrain bundle and 2 weeks later tissue was collected for measurement of the lesion size in the striatum (dopamine, DA, levels in the lesioned side expressed as a percentage of levels in the contralateral, unlesioned side) or substantia nigra pars compacta, SNc (the number of tyrosine hydroxylase immunoreactive, TH-IR, cells in the the lesioned side expressed as a percentage of levels in the contralateral, unlesioned side), as described in Table 1. Females: (A) GDX enhanced striatal DA loss and this effect was reversed by E2, not DHT, whereas (B), the loss of TH-IR cells in the SNc was unaffected by hormonal manipulations. Males: (C) GDX reduced striatal DA loss and this effect was reversed by E2, not DHT, whereas (D), the loss of TH-IR cells in the SNc was unaffected by hormonal manipulations. Values represent the mean ± s.e.m. (n = 6). ^* P < 0.05 versus gonad intact controls; ^# p < 0.05 versus GDX. Full details in Murray et al. (2003) and McArthur et al. (2007).

Fig. 2

Effects of hormonal environment on striatal dopamine transporter (DAT) levels in (A) female and (B) male rats. Bilateral gonadectomy (GDX) and hormone treatments were performed as described in Fig. 1. Specific binding density of the DAT ligand, [¹²⁵I]-RTI 121, was assessed by autoradiography 1 week later. DAT binding density was similar in control females at proestrus (Control Pro, high endogenous estradiol) and control males, and these values were significantly lower than those found in diestrus females (Control Di, low endogenous estradiol) and after GDX (males and females). Estradiol treatment (GDX + E2) suppressed DAT binding density to proestrus levels in females and to control levels in males. Values represent the mean ± s.e.m. (n = 6). ^* P < 0.05 versus Control Pro (females), controls (males) or GDX + E2 (males and females). Full details in McArthur et al. (2007).

Fig. 3

Hypothetical schema for estrogenic influences on compensatory mechanisms in striatal terminals of surviving neurons in the damaged nigrostriatal dopaminergic system. (A) As indicated by the arrows, in females, but not in males, estradiol (E2) enhances dopamine synthesis, release and turnover, whilst suppressing DAT levels and re-uptake of the neurotransmitter from the synaptic cleft. (B) This preserves striatal function when lesion size is small/moderate (⩽50%), but fails to do so as lesions increase, allowing motor symptoms to become manifest. This action of E2 in females may render them more able to delay progression, or even onset, of disease.

Fig. 4

Estradiol enhances microglial phagocytosis. Co-cultures of the murine microglial BV2 cell line and the dopamine-producing neuron-like PC12 cells were used as a model to investigate hormonal influences on microglial phagocytosis of apoptoic neurons (McArthur et al., 2010). (A) Treatment of BV2 microglia for 16 h with 100nM 17β-estradiol had no effect on the phagocytosis of vehicle-treated, non-apoptotic PC12 cells, but significantly increased the number of microglia phagoytosing apoptotic 6-OHDA-treated PC12 cells. ^* P < 0.05 versus untreated BV2 cells. (B) Example of BV2 microglia phacocytosing CMFDA-labelled green fluorescent PC12 cell treated with 6-OHDA.