Parkinson’s disease (PD) is a debilitating neurodegenerative disorder, impairing the motor functions of millions of elderly people worldwide.
Often, people with PD will experience disturbances in gastrointestinal function, such as constipation, years before motor symptoms set in.
Postmortem examinations of the brains of people with PD have shown that their brain cells that control movement are littered with aggregates, or clumps, of a protein called alpha-synuclein (α-Syn).
Now, working with mouse models, Caltech researchers have seeded α-Syn aggregates in neurons in the gut and discovered that these clumps can travel up to affect neurons in the brain—but this process depends on age.
Normally, mice produce an enzyme that is able to break down these clumps, but as they get older, they may lose this ability, which could explain why PD develops most often in elderly people.
The researchers showed that injecting mice with systemic delivery vectors carrying genes that encode for this enzyme helped ameliorate some of the clumping and partially restored proper gut function.
A paper describing the research appears in the February 17 issue of the journal Nature Neuroscience.
The work was led by researchers in the laboratory of Viviana Gradinaru (BS ’05), professor of neuroscience and biological engineering, Heritage Medical Research Institute Investigator, and director of the Center for Molecular and Cellular Neuroscience at the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.
As α-Syn aggregates have also been found in neurons in the intestines of people with PD, some researchers hypothesize that α-Syn aggregation begins first in the nervous system of the gut.
The idea is that the protein aggregates then hop from neuron to neuron, traveling from the gut nervous system up the vagus nerve and into the brain, seeding the formation of additional aggregates along the way.
“The vagus nerve is a physical connection between neurons in the gut and neurons in the brain.
If these damaging protein clusters first originate in gut neurons, then in the future we may be able to diagnose PD earlier and potentially use gene delivery to restore functions to the cells so that they can clean up the aggregates,” says Collin Challis, former postdoctoral scholar and first author on the study.
To test this, the Caltech team injected the gastrointestinal lining of mice with αSyn aggregates and then monitored the aggregates to see if they were progressing up to the brain stem.
In adult mice, the team did find progression of αSyn clusters, but they did not see the development of motor impairments.
The αSyn clusters also progressed in elderly mice (about 16 months old), but these mice exhibited both gastrointestinal disturbances – impaired gastric motility and fecal pellet hydration – and motor symptoms.
The question for the team, says Challis, was why these aggregates cause motor disturbances in older mice, whereas younger animals are not affected. “As we get older, we’re not as efficient at dealing with pathogens or misfolded proteins. Parkinson’s disease may be an example of this,” he says.
It was known that the enzyme glucocerebrosidase (GCase) has the ability to break down αSyn clusters.
This enzyme is naturally produced by mice – and an analog works similarly in humans – but if a mouse loses the ability to make it, αSyn proteins begin to cluster together.
The Gradinaru laboratory develops and utilizes viral vectors to deliver desired genes into specific cells through a non-invasive injection into the bloodstream.
Here, genes for three fluorescent proteins are delivered by viral vectors into cells in the gastrointestinal nervous system.
This technology can be used for labeling and imaging cells, as seen here, or to deliver genes that could ameliorate diseases. Image is credited to Gradinaru laboratory / Caltech.
To study GCase’s effect on PD-related symptoms, the team used mice that were genetically engineered to overproduce αSyn and injected the animals with genes that encode for GCase.
These genes were packaged in a variant of adeno-associated virus (AAV), a harmless viral shell that was previously engineered by the Gradinaru lab as a kind of delivery vehicle to get genetic material into gut cells via the bloodstream.
The team found that GCase partially restored normal gut function in these mice and decreased the aggregates in gut neurons.
“Mutations in the gene that encodes GCase are responsible for Gaucher disease and a risk factor in PD. Our work shows that this gene can be delivered by AAVs to rescue gastric symptoms in mice, and emphasizes that peripheral neurons are a worthwhile target for treating PD, in addition to the brain,” Gradinaru says.
A paper describing the research is titled “Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice.”
In addition to Challis and Gradinaru, additional co-authors are graduate student Acacia Hori; former postdoctoral scholar Timothy Sampson; graduate student Bryan Yoo; former postdoctoral scholar Rosemary Challis; Adam Hamilton of the Emory University School of Medicine in Atlanta; Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and Heritage Medical Research Institute Investigator; and Laura Volpicelli-Daley of the University of Alabama.
Funding: Funding was provided by the National Institutes of Health, the Department of Defense, the Heritage Medical Research Institute, the Pew Charitable Trusts, the Rogers Fellowship for Parkinson’s Research, and the CZI Neurodegeneration Challenge Network. Mazmanian and Gradinaru are affiliated faculty members with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.
Parkinson’s disease (PD) is the second most common, age-related neurodegenerative disorder, affecting about 3% of the population by the age of 65 and up to 5% of the people over 85 years [1]. The main pathological feature of PD is the progressive loss of midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of alpha-synuclein positive cytoplasmic inclusions, termed Lewy bodies, in surviving neurons [2].
Degeneration of the nigrostriatal DA pathway leads to the primary motor symptoms of PD, which include bradykinesia, rigidity, resting tremor and gait disturbances. The most common non-motor symptoms associated with the disorder include autonomic dysfunctions, cognitive abnormalities, psychiatric symptoms such as anxiety, depression and apathy, and sleep disorders with high prevalence of insomnia and REM behavior disorder [3].
The vast majority of PD cases occur sporadically, only 10% of patients carrying disease-causing genetic mutations.
Together with aging, genetics, environment and immune status, the role of biological sex as an important factor in the development of PD has been widely discussed in the past decade.
There are clear sex-related differences in epidemiological and clinical features of the disease: PD affects men twice more often than women [4, 5], but women have a higher mortality rate and faster progression of the disease [6].
Moreover, women show distinctive symptoms as well as differences in the response to pharmacological therapies and deep brain stimulation procedure, and in the personal evaluation of the quality of life compared with men [7].
Although women diagnosed with PD are a sizable portion of the PD population, their specific needs are still partially overlooked.
A retrospective observational study looking at Medicare data— a government-financed health insurance program for the elderly and disabled in the United States— highlighted that women are less likely to have specialist (neurologist) care, together with nonwhites [8].
Accordingly, an a posteriori analysis of multiprofessional treatment approach PD-MCT (i.e., “Parkinson’s disease multimodal complex treatment”) conducted in Germany in the years 2010– 2016 and involving pharmacological and non-pharmacological treatment options such a physical therapy, occupational therapy, and speech therapy, revealed that more male than female patients were treated under this program [9].
A recent study covering 7209 patients at 21 centers in the United States, Canada, the Netherlands, and Israel, disclosed that women are also less likely than men to have informal caregiver support (i.e., support from spouse, family or friends). As a result, more women use paid caregiver services than men.
The reasons for this discrepancy may be linked to the longer average lifespan of women and their natural inclination toward being caregivers rather than receivers of care, even when their spouse or caregiver is still present in their lives [6].
Studies considering female sex as a crucial variable to consider are highly under-represented in PD research. In line with this, a notice disseminated by the National Institutes of Health in 2015 exhorts scientists to factor sex into the design, analysis and reporting of vertebrate animal and human studies (NOT-OD-15-102).
Together with the NIH initiative, the World Health Organization (WHO) also stated the necessity of the “adequate demographic (including gender) characterization, analysis and assessment of the patient population together with separate ICH (International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guideline on women as a special population in clinical trials” as the priority for European and world medicine [10].
This review summarizes the most recent knowledge concerning differences between women and men in PD clinical features, PD risk factors, response to treatments and mechanisms underlying the disease pathophysiology.
CLINICAL DIFFERENCES
According to a recent meta-analysis, an age-related rising incidence of PD is observed in both sexes, but with a steeper increase in males in the 60– 69 and 70– 79 decades of life [11]. The increasing prevalence of PD in men is reported both for disease with and without dementia [12].
Sex-based differences have been also found for factors that influence life prognosis in PD. A recent study, using relative survival methods, showed that a diagnosis of PD with dementia has a larger impact on life expectancy in females than in males [13]. Park and colleagues demonstrated that a low body mass index (<18.5) is strongly associated with reduced survival time, but this reduction is significant only in males [14].
In addition to the differences between women and men in PD prevalence and prognosis, many studies have reported sex-related differences in the clinical phenotype (Fig. 1).
Motor symptoms
PD diagnosis is essentially based on the presence of motor symptoms. The characterization of possible sex-related differences in motor symptom patterns may play a crucial role in terms of diagnostic accuracy and therapeutic strategies.
Over the past decades, the effect of biological sex on the expression and severity of PD motor symptoms has been broadly discussed in the literature. Motor symptoms emerge later in women, with specific characteristics such as reduced rigidity [15], tremor as a more common first presenting symptom [16], higher propensity to develop postural instability and elevated risk for levodopa-related motor complications [17].
Male sex, on the other hand, has been recently associated with later development of freezing of gait— the most disabling motor complication of PD [18]— whereas female sex was mentioned in the list of predictors of progression to falling in PD [19].
Another specific motor disturbance of PD is camptocormia, which refers to abnormal severe forward flexion of the trunk that occurs while standing or walking and abates or disappears in a supine position.
It has been recently reported that PD male patients have higher risk of developing this symptom along the disease progression [20]. An ongoing clinical trial is evaluating the prevalence in PD and the biological sex impact on other postural abnormalities, such as Pisa syndrome, antecollis, scoliosis and striatal deformities related to hand and/or toes (ClinicalTrials.gov Identifier: NCT03573232).
Non-motor symptoms
Martinez-Martin and colleagues performed a complex study in a cohort of 951 PD patients to assess the prevalence and severity of non-motor symptoms according to biological sex. They concluded that symptoms such as fatigue, depression, restless legs, constipation, pain, loss of taste or smell, weight change and excessive sweating are more severe and common in women [21].
The relationship between female sex and pain has been recently confirmed in a large clinical study demonstrating that, together with affective and autonomic symptoms, motor complications and younger age, female sex predicts overall pain severity [22].
A clinical trial designed to study the pathophysiology underlying spontaneous and evoked pain in PD patients with motor fluctuations is currently ongoing (NCT03648671); among other factors, the trial aims to evaluate the impact of biological sex on the quality and distribution of different pain syndromes associated with PD.
Within the autonomic disturbances occurring in PD, gastrointestinal dysfunctions play a major role, also because of their profound impact on the quality of life.
Based on the evidence that intestinal inflammation is consistent with intestinal symptoms and may act as a driver of disease pathology, Housers and colleagues conducted an extensive analysis of immune and angiogenetic factors in stool of PD patients and healthy controls.
They found disease-associated increase in numerous immune and angiogenesis mediators, but only in the stool of female PD patients while the stool of male patients did not differ significantly from controls [23]. Female PD patients have also shown higher predisposition to develop critical dysphagia [24], whereas male patients are more prone to severe drooling [25].
Different studies showed that male PD patients have worse general cognitive abilities and male sex is the primary predictive factor for mild cognitive impairment and its more rapid progression in the severe stage of the disease [26– 28].
Accordingly, female PD patients perform better at the Symbol Digit Modalities Test, verbal fluency tests and overall cognition measured by the Montreal Cognitive Assessment scale, but present with worse visuospatial function [29]. Significant sex differences are also observed for frontal executive abilities (attention and working memory), with male PD patients showing greater deficits than female non-demented patients.
Regarding PD-associated complications, female sex is associated with more severe, persistent and episodic anxiety and profound depression [30, 31], whereas impulse control disorders, such as pathological gambling and hypersexuality, are more common in male PD patients [32– 34].
Nevertheless, men show greater sexual dysfunction and impairment of their sexual relationship than women [35]. Biological sex also differently impact on emotion processing in PD with men showing worse recognition performance of the emotion anger accompanied by reduced neural response [36].
REM sleep behavior disorder (RBD), the strongest known prodromal symptom of neurodegenerative synucleinopathies, is classically associated with male sex [37]. However, a recent large population-based study reverted the traditional RBD clinical profile showing no difference between men and women [38]. Women generally show less aggressive and injurious RBD than men, thus they are less prone to present for medical attention. According to the authors, this factor might have introduced a bias in the previous studies.
Quality of life
Gender also affects how clinical symptoms affect quality of life of PD patients and their ability to perform activities of daily living, to participate in social activities and to access medical care. The health-related quality of life (HrQoL) is a multi-dimensional scale used to evaluate the impact of disease and treatments on the lives of patients.
A recent study exploring the relationship between three HrQoL domains (physical-functioning, cognition, socioemotional) and sociodemographic variables did not reveal a global gender effect [39]. However, female gender proved to be a negative predictor for physical-functioning and socioemotional HrQoL, whereas male gender mainly affected the HrQoL cognition domain.
Conversely, in a prospective study on a cohort of patients with idiopathic PD in Germany, female patients reported more problems in all dimensions, except selfcare [40]. At the same time, a longitudinal study designed to analyze the effect of PD onset on life satisfaction showed marked reduction of life satisfaction among individuals in the second half of life in men, but not in women [41].
DISEASE PREDICTORS AND RISK FACTORS
The etiology of PD is not well understood. Despite the presence of familial cases, PD is substantially an idiopathic, multi-factorial disease caused by the interplay between genetic and environmental factors. Genetic studies have identified increasing numbers of risk polymorphisms, whereas little is still known about environmental risk factors and how these affect PD risk.
Heinzel and coll. recently highlighted the sex-related differences in prodromal PD. They concluded that women and men show distinctive prodromal markers of PD (subthreshold parkinsonism, constipation, olfactory loss, depression, probable RBD, nonsmoking, nonuse of caffeine, nigral hyperechogenicity), suggesting that these differences should be taken into account to guarantee the diagnostic accuracy of prodromal PD [42].
Genetic risk factors
Urate, an endogenous purine metabolite with antioxidant and neuroprotectant properties, is a genetically and environmentally determined modifiable factor and a potential PD biomarker, as high urate levels are associated with reduced risk and slower progression of idiopathic PD [43, 44]. However, the contribution of urate levels to PD risk according to biological sex is still controversial.
Higher urate levels were associated with reduced prevalence and slower progression of PD in men, while the opposite trend was observed in women [45, 46]. More recently, a large population-based study conducted in Norway demonstrated that the treatment with urate-lowering drugs correlates with lower PD risk especially in men, even if no statistically significant difference by sex was detected. In addition, the association varied significantly by age among women, showing a protective effect only in women above 70 years, when urate levels are comparable to those in men [47].
The neuroprotective effect of urate in men, especially in terms of cognitive functions, seems to be related to its ability to influence resting-state networks (RSN), which reflect the spontaneous neural activities and provide indirect information regarding brain functional status [48]. Interestingly, a recent study focused on the potential of urate plasma levels in subject carrying mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) [49], the most common genetic cause of PD [50].
The study demonstrated that subjects with a LRRK2 mutation who had not developed PD had higher urate levels than LRRK2-PD subjects; moreover, a significant difference in urate levels between control subjects and PD patients was observed among women with LRRK2 mutations [49].
The strength of the urate association observed in both women and men with LRRK2 mutations may help to explain the comparable PD penetrance of LRRK2 mutations between sexes, in contrast to the well-established lower risk of idiopathic PD in women. Although this seems to be valid for the most part of variants in LRRK2, a recent meta-analysis highlighted that carriers of LRRK2 G2019S variant are predominantly females [51] and show sex-dependent phenotypic differences, with cognitive impairment and depression being less common in G2019S male carriers compared with females.
The association between mutations in GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), and PD development has highlighted the potential role of mutations in lysosome-related genes as risk factors for PD. Since lysosomes are involved in the degradation of alpha-synuclein, lysosomal dysfunction could trigger alpha-synuclein accumulation, thus contributing to PD pathogenesis [52].
Alcalay and coll. showed a link between PD status and reduced activity of galactosidase alpha (GLA), a lysosomal enzyme encoded by a gene on the X chromosome whose mutations cause Fabry’s disease. Differently from GCase, this association should be sex-dependent, reaching significance among women only [53].
Lastly GAPDH gene, encoding a highly conserved protein involved in various cellular processes (e.g., glycolysis metabolism, mitochondria damage, autophagy) was identified as another gene with a potential role in PD [54]. Ping and coll. showed that rs1136666 polymorphism of GAPDH strongly correlates with sporadic PD and increases PD risk in older male [55].
Environmental risk factors
One of the most prominent environmental factors connected to elevated PD risk is chronic stress [56]. Adverse psychosocial work conditions are a potential source of stress relevant for public health, which can be described by the “job demand-control” model.
This model consists of two dimensions: the “demand component” measuring time pressure and psychological/cognitive demands and the “control component” including decision making authority and skill discretion abilities.
A recent study on the association between occupational stress according to this model and the risk for PD showed that high job demands appear to increase PD risk in men, especially in men with high education, whereas high job control increases PD risk more strongly in low educated women [57].
Occupational exposure to environmental factors with neurotoxic potential has received considerable attention in the PD field. Increased risk of PD has been classically reported in specific occupational groups, including farmers, wood workers, painters, metallurgy and medical workers exposed to pesticides, solvents and metals [58].
A recent nationwide study conducted in France, based on a comprehensive analysis of industry sectors, showed a significant association between PD incidence and specific sectors (e.g., agriculture, metallurgy, textile). However, the difference in the distribution of occupations and exposure patterns between men and women complicate the realistic assessment of gender-related impact of this risk factor [59].
A recent population-based, longitudinal large-scale cohort study conducted in statin-free individuals examined the association between cholesterol levels and PD risk. The authors found that total cholesterol levels greater than 180 mg/dL and low-density lipoprotein cholesterol levels greater than 110 mg/dL are associated with a decreased risk of PD in middle-aged men and elderly women [60].
The age-pooled analyses also showed a significantly reduced PD risk for men, but not for women. Given the absence of the potentially confounding effect of statin use, this study could provide a relevant contribution in clarifying the controversial relationship between cholesterol and PD. Although the study was not designed to provide mechanistic information, the authors suggested a modulatory effect of sex hormones on lipoprotein metabolism and apolipoprotein E phenotype.
Physical activity is another important lifestyle factor that may affect PD onset, severity and progression. High levels of exercise in midlife are associated with lower PD risk, better disease prognosis and lower rates of serious complications [61]. A large international multicenter cohort study on early PD patients showed that higher self-reported activity scores were associated with younger age and male gender. Older patients, especially women, may be particularly vulnerable to inactivity and its complications [62].
MPACT OF BIOLOGICAL SEX ON PD PATHOPHYSIOLOGY
The distinctive clinical features as well as the contribution of different risk factors support the idea that PD development might involve distinct pathogenetic mechanisms (or the same mechanism but in a different way) in male and female patients. It is clear that estrogens play a preponderant role in the sex differences in PD, providing disease protection as demonstrated by the similar incidence of the disease in men and post-menopausal women.
Moreover, it is noteworthy that sex hormones act throughout the entire brain of both males and females and sex differences are now highlighted in brain regions and functions not previously considered as subjected to such differences, opening the way to a better understanding of gender-related behavior and functions.
This section presents an overview of the most recent evidence corroborating the hypothesis of a sex-related PD pathophysiology, with a special focus on the role of estrogens (Fig. 2).
Dopaminergic neurodegeneration
Dopaminergic neurons in the substantia nigra are highly vulnerable to stress conditions, compared to other neuronal types. This vulnerability is ascribable to different factors, such as high oxidative burden during dopamine metabolism, excitotoxicity, high iron content and low mitochondrial mass. Consequently, sex differences in these factors may account for the different propensity of dopaminergic neurons to degenerate.
Gene expression studies in human SNc dopamine neurons of control and PD subjects revealed a sex-specific genomic signature: genes that are upregulated in females are mainly involved in signal transduction and neuronal maturation, while in males upregulated genes encode proteins involved in PD pathogenesis, such as alpha-synuclein and PINK1 [87, 88].
Together with differential gene expression, a stereological analysis of dopamine receptor 1 (D1) and 2 (D2) distribution during development highlighted maturational changes in the expression of these receptors between the sexes.
In particular, females had a higher D1:D2 ratio compared to males in all regions analyzed (including dorsal and ventral striatum) except for the insular cortex, suggesting that D1 dominance may make one resilient to some disorders (e.g., addiction) but vulnerable to others (e.g., anxiety) [89].
Female dopaminergic cells generally show lesser vulnerability to factors inducing degeneration than male neurons. Accordingly, reserpine-treated female rats did not show any reduction of tyrosine hydroxylase immunoreactivity in the SNc and dorsal striatum compared to males [90].
The lack of Ras homolog enriched in striatum (Rhes), a protein that exert pleiotropic effects on cell function, in KO mice induced a decrease in tyrosine hydroxylase expression in males only, while KO females showed resistance to DA neuron degeneration, which tended to decrease only with aging [91, 92].
Interestingly, neuronal loss in male SNc is accompanied by a significant reduction in total ganglioside content, especially neuronal- or synaptic-enriched gangliosides GD1a and GT1b. No significant abnormalities were found in female PD subjects [93]. Accordingly, it has been demonstrated that estradiol acts as homeostatic modulator of lipid rafts, thus preserving lipid balance in neuronal membrane microdomains [94].
The specific impact of estradiol on dopamine metabolism mainly accounts for the reduced vulnerability observed in female brain. It is well known that estradiol increases the synthesis, release, reuptake and turnover of DA. Moreover, this hormone potentiates amphetamine-stimulated DA release in the dorsolateral striatum in ovariectomized rats by interaction with estradiol and mGlu5 receptors [95].
Nevertheless, Conway and coll. demonstrated that dopamine production and release in female rats can also be independent by estrogens and provide protection from kappa opioid receptors-mediated negative effects on brain stimulation reward [96].
Neuroinflammation
Neuroinflammation is an important piece of the pathogenic puzzle of PD. Current evidence suggests that the physiological role exerted by microglial and astrocytic cells could become compromised during aging, thus contributing to PD onset and progression [97– 100]. Since estrogens have anti-inflammatory properties, their actions throughout the lifespan could partially account for sex-related risk and manifestation of PD.
Transcriptomic analysis of male and female microglia isolated from adult healthy mice revealed that microglia is sexually differentiated and that its sensitivity and ability to respond to specific hormonal and environmental stimuli is affected by the neonatal estrogen priming which permanently induces a sexual phenotype that is maintained in the adult animals [101].
In particular, estrogen priming of male microglia changes their immune capacity by increasing the ability to react to inflammatory stimuli. Accordingly, Hanamsagar and coll. have demonstrated that the mechanisms driving development and immune reactivity in microglia are dissociable in males vs. females and that male microglial transcriptome is more developmentally mature than female microglia [102].
As mentioned before, postnatal sexual dimorphism persists in the adult brain, as demonstrated by the differences in the number and morphology of microglia in different anatomical regions (i.e., hippocampus, cortex and amygdala) between males and females [103, 104]. This heterogeneity may lead to development of distinct, sex-dependent microglia inflammatory responses in the brain. Several studies in animal models of PD showed that the neuroprotective and symptomatic effect of estrogens is due to their ability to attenuate microglia activation and to modulate microglia polarization toward a cytoprotective phenotype [105– 107].
Similarly to microglia, also astrocytes show sex differences under physiological and pathological conditions. Male and female cortical astrocytes respond differentially to an inflammatory challenge, such as a treatment with lipopolysaccharide [108], leading to increased levels of distinct inflammatory factors.
In detail, male astrocytes showed enhanced expression of IL6, TNFα and IL1β after LPS treatment whereas the levels of interferon-inducible protein 10 were higher in astrocytes derived from females. Further, a recent study demonstrated sex-dependent mitochondrial bioenergetic properties of rat cortical astrocytes, with male astrocytes having a higher maximal respiration than female astrocytes at low physiologically relevant oxygen tension [109].
Astrocytes participate in the protective actions of estrogenic compounds [110]. Recent findings point to the role of these inflammatory cells in mediating the effect of sex hormones on cognition.
The proven role of estrogens in hippocampal plasticity and the evidence of estrogen effects on memory, suggested a positive relationship between estrogens and cognition. Yun and coll. demonstrated that estrogens might protect against memory impairment through the regulation of neurogenic inflammation by inhibiting NF-κB activity [111].
Analogously, the reduction of estradiol level and the expression of its receptors in hippocampus of aged female rat has been shown to contribute to the deficit of spatial memory performance in the Morris water maze test [112]. Nevertheless, a recent paper recommended to carefully consider the positive effect of estrogens on cognition, suggesting that these hormones can enhance and impair learning depending on the memory system [113].
In this context, astrocytes would play the role of providers of metabolic substrates – especially lactate – during cognition, thus mediating the opposing effects of estrogens on learning. Most interestingly, a study on adult zebra finches indicates that astrocytes can increase estradiol synthesis through cytokine-dependent up-regulation of aromatase and release of cytokines; this, in turn, could alter metabolic and neural plasticity phenomena that are essential for learning and memory [114].
Oxidative stress
Different factors seem to contribute to oxidative stress in PD, including dopamine metabolism, mitochondrial dysfunction, iron overload, neuroinflammation, calcium dysregulation and aging.
In particular, given the vital functions exerted by mitochondria and the high metabolic rate and increased sensitivity to oxidative damages of the brain, the maintenance of mitochondrial homeostasis is central to neuronal viability and function.
Because of their exclusive maternal transmission, mitochondria exhibit a strong sex-specific behavior and exert differential effects in males and females. Gender indiscriminately impacts on all mitochondria functions. Studies conducted in animals and postmortem human samples showed that female neurons have higher electron transport chain activity and greater functional capacities compared with male neurons [115– 117].
Generally, lower oxidative stress and damage have been observed in brain mitochondria from female rats compared with males, independently of age and estrus cycle [115, 118]. Contrary to positive influence of female gender on cell respiration and generation of redox oxygen species, calcium uptake capacity is lower in female than male brain mitochondria [119], which can negatively affect mitochondrial calcium buffering and consequently cell homeostasis.
Mitochondria are both the site of steroidogenesis and target of sex-steroids in stimulating mitochondrial functions, especially biogenesis. Estradiol counteracted the loss of mitochondria in aged female hippocampus, restoring mitochondrial number to the levels observed in young animals [120]. G-1, an agonist of G protein-coupled estrogen receptor (GPER), reversed the reduction of estrogen receptors in the hippocampus of 16-month-old female rats, increased mitochondrial membrane potential and activity of anti-oxidant enzymes [121].
These effects are accompanied by a relief of anxiety and depression-like behavior suggesting GPER as a potential therapeutic target for estrogen deficiency-related affective disorders. Analogously, estradiol and the selective estrogen receptor modulators tamoxifen and raloxifene have been shown to reduce oxidative stress, apoptosis, mitochondrial membrane depolarization and Ca2+ influx through the inhibition of thermosensitive transient receptor potential (TRP) channels [122].
Nakano and coll. showed that esculetin, a small chemical with agonist action on all three estrogen-related receptors, enhances glycolysis and mitochondrial respiration when added to culture media of neuronally differentiated PC12 cells, leading to elevated cellular ATP levels [123]. Interestingly, the effects of estrogens are not restricted to neuronal cells as demonstrated by the protective outcomes of the treatment with tibolone— a synthetic steroid with estrogenic, progestogenic and androgenic actions— on astrocytic mitochondria [124].
Although the sexual dimorphism in brain mitochondria has been proven, few recent studies have dealt with sex-related differences of oxidative stress in the context of PD. Sex variance in prooxidant-antioxidant balance and malondialdehyde levels, a product of lipid peroxidation, has been observed in PD patients [125].
Interestingly, a recent neuromelanin (NM) imaging study highlighted a bigger normalized NM-rich volume in the women SN compared with men older than 47 years, suggesting that this difference may underpin the high male-to-female ratio of the PD prevalence [126].
Neuromelanin, a pigment with paramagnetic properties, acts as a scavenger removing potentially toxic substances through the autooxidation of catecholamines and/or binding redox-active metal ions such as iron.
The relationship between estrogens and iron in PD has been known for decades. Experimental and epidemiological evidence suggest that estrogens play a regulatory role in iron metabolism. Striatum of male mice has been shown more susceptible to iron accumulation than female [127].
Analogously, a study conducted on humans showed that at the same plasmatic concentrations of iron, women had a lower probability of having PD [128]. Recently, it has been clarified that estradiol-related effects on iron metabolism exploit different pathways between the sexes, with GPER1 mediating the suppressive effects of estradiol on iron overload-induced autophagy in males while estrogen receptor α on induced lipid peroxidation in females [129].
Moreover, Xu et al., discovered a cell-dependent regulation of iron metabolism by estrogens. According to these findings, estrogen would increase the expression of iron exporter ferroportin 1 (FPN1) and iron importer divalent metal transporter 1 (DMT1) in astrocytes, whereas the down-regulation of iron regulatory protein may account for the decreased DMT1 and increased FPN1 expression in neurons [130].
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