Parkinson’s disease; meta-analysis; sex differences; sexual dimorphism
Résumé :
[en] Parkinson’s disease (PD) is a heterogeneous disorder, and among the factors which influence the symptom profile, biological sex has been reported to play a significant role. While males have a higher age-adjusted disease incidence and are more frequently affected by muscle rigidity, females present more often with disabling tremors. The molecular mechanisms involved in these differences are still largely unknown, and an improved understanding of the relevant factors may open new avenues for pharmacological disease modification.
To help address this challenge, we conducted a meta-analysis of disease-associated molecular sex differences in brain transcriptomics data from case/control studies. Both sex-specific (alteration in only one sex) and sex-dimorphic changes (changes in both sexes, but with opposite direction) were identified. Using further systems level pathway and network analyses, coordinated sex-related alterations were studied. These analyses revealed significant disease-associated sex differences in mitochondrial pathways and highlight specific regulatory factors whose activity changes can explain downstream network alterations, propagated through gene regulatory cascades. Single-cell expression data analyses confirmed the main pathway-level changes observed in bulk transcriptomics data.
Overall, our analyses revealed significant sex disparities in PD-associated transcriptomic changes, resulting in coordinated modulations of molecular processes. Among the regulatory factors involved, NR4A2 has already been reported to harbour rare mutations in familial PD and its pharmacological activation confers neuroprotective effects in toxin-induced models of Parkinsonism. Our observations suggest that NR4A2 may warrant further research as a potential adjuvant therapeutic target to address a subset of pathological molecular features of PD that display sex-associated profiles.
Disciplines :
Sciences du vivant: Multidisciplinaire, généralités & autres
Auteur, co-auteur :
TRANCHEVENT, Leon-Charles ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
HALDER, Rashi ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services
GLAAB, Enrico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Co-auteurs externes :
no
Langue du document :
Anglais
Titre :
Systems level analysis of sex-dependent gene expression changes in Parkinson’s disease
Date de publication/diffusion :
2023
Titre du périodique :
NPJ Parkinson's Disease
eISSN :
2373-8057
Maison d'édition :
Nature Publishing Group, New-York, Etats-Unis - New York
Volume/Tome :
9
Fascicule/Saison :
8
Peer reviewed :
Peer reviewed vérifié par ORBi
Focus Area :
Systems Biomedicine
Projet FnR :
FNR11651464 - Multi-dimensional Stratification Of Parkinson'S Disease Patients For Personalised Interventions, 2017 (01/07/2018-30/06/2021) - Enrico Glaab
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