Park7 deletion leads to sex-specific transcriptome changes involving NRF2-CYP1B1 axis in mouse midbrain astrocytes

npj Parkinson s Disease, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 4, 2025

Abstract Loss-of-function mutations in PARK7 , encoding for DJ-1, can lead to early onset Parkinson’s disease (PD). In mice, Park7 deletion leads dopaminergic deficits during aging, and increased sensitivity oxidative stress. However, the severity of reported phenotypes varies. To understand molecular changes upon loss we performed transcriptomic profiling midbrain sections from young mice. While at 3 months transcriptomes both male female mice were unchanged compared their wildtype littermates, an extensive deregulation was observed 8 month-old males. The affected genes are involved processes like focal adhesion, extracellular matrix interaction, epithelial-to-mesenchymal transition (EMT), enriched primary target NRF2. Consistently, antioxidant response altered specifically DJ-1 deficient Many misregulated known estrogen retinoic acid signaling show sex-specific expression Depletion or NRF2 astrocytes recapitulated many vivo changes, including downregulation CYP1B1, enzyme metabolism. Interestingly, knock-down CYP1B1 led gene adhesion EMT astrocytes. Finally, iPSC-derived with function mutation also showed pathway genes. Taken together, our data indicate that through astrocytic alterations NRF2-CYP1B1 axis, suggesting higher males DJ-1.

Language: Английский

Exploring the Regulation of Cytochrome P450 in SH-SY5Y Cells: Implications for the Onset of Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7439 - 7439

Published: July 6, 2024

Human individual differences in brain cytochrome P450 (CYP) metabolism, including induction, inhibition, and genetic variation, may influence sensitivity to neurotoxins thus participate the onset of neurodegenerative diseases. The aim this study was explore modulation CYPs neuronal cells. experimental approach focused on differentiating human neuroblastoma SH-SY5Y cells into a phenotype resembling mature dopamine neurons investigating effects specific CYP isoform induction. results demonstrated that differentiation protocols using retinoic acid followed by phorbol esters or brain-derived neurotrophic factor successfully generated with morphological characteristics increased markers (NeuN, synaptophysin, β-tubulin III, MAO-B). qRT-PCR Western blot analysis showed expression 1A1, 3A4, 2D6, 2E1 isoforms detectable undifferentiated cells, subsequent increases 2E1, 1A1 following differentiation. Further β-naphthoflavone treatment 2D6 ethanol were evident. These demonstrate can be modulated suggest their potential as an model investigate role processes involved development

Language: Английский

SNPs in cytochromes P450 catalyzing cholesterol degradation in brain are associated with Parkinson’s disease

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 30, 2024

Besides being an essential structural component of plasma membranes and the precursor many functional compounds signaling molecules, cholesterol was also proposed to play a role in etiology and/or manifestation Parkinson’s disease (PD). However, so far systematic investigations on its metabolites present brain for PD are missing. Here, we investigate first time association with SNPs genes four cytochromes P450 (P450), CYP46A1, CYP39A1, CYP27A1 CYP7B1, which critical degradation brain. Analyzing 1,349 individuals from PPMI data base, found 24 these genes, significantly over- or under-represented patients suffering idiopathic (IPD). Studying each 362 IPD individually, that most (45%) showed only one associated SNP while 31% displayed two 18% three SNPs. The occurrence some is same order magnitude as GBA (beta-glucocerebrosidase) thus might reflect genetic predisposition PD. As all were located introns 3′ untranslated regions, evaluated prospective regulatory impact surrounding genomic regions by using transcriptome epigenome Foundational Data Initiative Parkinson Disease (FOUNDIN-PD). FOUNDIN-PD provides gene expression, open chromatin DNA methylation cohort 89 induced pluripotent stem cell (iPSC) lines differentiated dopaminergic (DA) neurons derived people study. Indeed, SNPs, CYP7B1 (rs118111353) other (rs74446825), localized within region neurons. Interestingly, iPSC rs118111353 reference allele. P450, expressed neurons, discuss further studies connect expression levels. Finally, potential possibilities personalized therapeutic treatment investigated discussed.

Language: Английский