Sex-Specific Transcriptome Differences in Substantia Nigra Tissue: A Meta-Analysis of Parkinson’s Disease Data

Mariani, Elisa; Lombardini, Lorenza; Facchin, Federica; Pizzetti, Fabrizio; Frabetti, Flavia; Tarozzi, Andrea; Casadei, Raffaella

doi:10.3390/genes9060275

Cited by 17 publications

(14 citation statements)

References 77 publications

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“…Some GEO series were not included in TRAM analysis, as previously described [ 42 ], for the following criteria of exclusion: data from exon array or other probes (an extremely high number of data rows could interfere with program execution); the absence of identifiers corresponding to those found in the GEO sample records (GSM); platforms with an atypical number of genes (i.e., <5000 or >60,000); data with expression values not explicitly stated as linear or logarithmic.…”

Section: Methodsmentioning

confidence: 99%

“…For instance, the expression of the Y-linked SRY gene activates a specific set of genes for testes formation, as SOX9 and FGF9 both in mice and humans, and, at the same time, represses female specific genes as WNT4 [ 37 ]. At least in mouse, the major molecular differences between sexes in gene expression are in gonadal tissues [ 26 , 38 ], but diversity occurs also in the other organs as recently reported by Gershoni and Pietrokovski [ 39 ] and are well documented in liver [ 40 ], brain [ 41 , 42 ] and heart [ 43 ]. Moreover, according to a recent study, some of the imprinted genes closely associated with the control of fetal growth rates and expressed in the hypothalamus, an important target for gonadal hormones, seem to be controlled or at least affected, by sexual differentiation and interestingly exhibit different sexual expression [ 44 ].…”

Section: Introductionmentioning

confidence: 99%

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Sex-Specific Transcriptome Differences in Human Adipose Mesenchymal Stem Cells

Bianconi

Casadei

Frabetti

et al. 2020

Genes

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In humans, sexual dimorphism can manifest in many ways and it is widely studied in several knowledge fields. It is increasing the evidence that also cells differ according to sex, a correlation still little studied and poorly considered when cells are used in scientific research. Specifically, our interest is on the sex-related dimorphism on the human mesenchymal stem cells (hMSCs) transcriptome. A systematic meta-analysis of hMSC microarrays was performed by using the Transcriptome Mapper (TRAM) software. This bioinformatic tool was used to integrate and normalize datasets from multiple sources and allowed us to highlight chromosomal segments and genes differently expressed in hMSCs derived from adipose tissue (hADSCs) of male and female donors. Chromosomal segments and differentially expressed genes in male and female hADSCs resulted to be related to several processes as inflammation, adipogenic and neurogenic differentiation and cell communication. Obtained results lead us to hypothesize that the donor sex of hADSCs is a variable influencing a wide range of stem cell biologic processes. We believe that it should be considered in biologic research and stem cell therapy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex-Specific Transcriptome Differences in Human Adipose Mesenchymal Stem Cells

Bianconi

Casadei

Frabetti

et al. 2020

Genes

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“…Genetic studies have demonstrated that sex influences PD risk where the presence of a Y chromosome increases risk by 1.5 (Wooten et al, 2004). Additionally, sex-biased expression of genes related to neuron and immune function have been identified in nigral tissue of PD patients (Mariani et al, 2018). Yet the impact of sex on immune system responses and how the latter affect development of PD is not known.…”

Section: Introductionmentioning

confidence: 99%

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

Joers

Masilamoni

Kempf

et al. 2020

Preprint

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Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [ 18 F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

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“…Alterations in PD gene expression have been described [9, 10], both in experimental models and in humans[11–16],however, the expression of genes associated with the hDAT interactome and functional partner in Parkinson’s disease remains poorly understood [17]. A better understanding of how changes in gene expression in the hDAT interactome in PD could help clarify its role in the development of this disease and guide advances in drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Differential gene expression in the interactome of the Human Dopamine transporter in the context of Parkinson’s disease

Navarro

Scott

Philot

et al. 2020

Preprint

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Background: The human dopamine transporter is the main regulator of dopamine tone and an intricate network exists to regulate the expression, conformation, and kinetics of the hDAT. hDAT dysfunction is directly related to Parkinson's disease. The objective of this work is to evaluate the differential gene expression in the interactome of the Dopamine transporter in the context of Parkinson's disease. Methods:To do this, we evaluated hDAT interaction data in string-db, mint.bio, IntAct, reactome, hprd and BioGRID, subsequently, data was obtained from the differential gene expression of mRNA and miRNAs for this hDAT interactome in the context of PD. Results: The analysis of the differential expression changes of genes of the hDAT interactome in tissues of patients with PD compared with tissues of individuals without PD, allowed to identify an expression pattern of 32 components of the hDAT interactome, of which 31 presented a negative change proportion in PD. Conclusions: We found a total of 90 miRNAs that could regulate the expression of 27 components of the hDAT interactome, at the same time, 39 components of the hDAT interactome may participate in 40 metabolic pathways. Together, these findings show a systematic effect on the hDAT-mediated dopamine internalization process in patients with Parkinson's, which would contribute to a greater susceptibility to neuronal oxidative stress in PD patients.

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Sex-Specific Transcriptome Differences in Substantia Nigra Tissue: A Meta-Analysis of Parkinson’s Disease Data

Cited by 17 publications

References 77 publications

Sex-Specific Transcriptome Differences in Human Adipose Mesenchymal Stem Cells

Sex-Specific Transcriptome Differences in Human Adipose Mesenchymal Stem Cells

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

Differential gene expression in the interactome of the Human Dopamine transporter in the context of Parkinson’s disease

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