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

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The Etiology of Parkinson’s Disease: New Perspectives from Gene-Environment Interactions

Journal of Parkinson s Disease, Journal Year: 2023, Volume and Issue: 13(8), P. 1281 - 1288

Published: Nov. 17, 2023

Parkinson’s disease is now the most rapidly growing neurodegenerative worldwide. It therefore critical to identify which factors, and what extent, contribute multifactorial etiology of disease. Here, we address two interesting elements from perspective genetics, namely (a) estimated age several genetic risk factors related disease; (b) relative contribution genetics disease, as derived twin studies. Based on these perspectives, argue that are by themselves insufficient explain majority environmental required for become pathophysiologically relevant.

Language: Английский

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Cytochrome P450 monooxygenase systems: diversity and plasticity for adaptive stress response

Progress in Biophysics and Molecular Biology, Journal Year: 2024, Volume and Issue: 193, P. 19 - 34

Published: Sept. 6, 2024

Language: Английский

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Environmental Risk Factors for Parkinson's Disease: A Critical Review and Policy Implications

Movement Disorders, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

Abstract The age‐standardized prevalence of Parkinson's disease (PD) has increased substantially over the years and is expected to increase further. This emphasizes need identify modifiable risk factors PD, which could form a logical entry point for prevention PD. World Health Organization (WHO) recommended reducing exposure specific environmental that have been reported be associated with in particular pesticides, trichloroethylene (TCE), air pollution. In this review we critically evaluate epidemiological biological evidence on associations these PD whether putative are causal. We conclude when considered isolation, it difficult determine causal, large part because decades‐long lag between relevant exposures incidence manifest However, tandem from complementary research lines (such as animal models), increasingly likely reflect harmful causal effects. Fundamentally, whilst highlight some gaps require further attention, believe current base sufficiently strong enough support our call stronger policy action. © 2024 Author(s). Movement Disorders published by Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Language: Английский

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The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson’s disease

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(2), P. e3002974 - e3002974

Published: Feb. 18, 2025

Parkinson’s disease (PD) is a neurodegenerative characterized by the death of dopaminergic neurons in substantia nigra and formation Lewy bodies that are composed aggregated α-synuclein (α-Syn). However, factors regulate α-Syn pathology nigrostriatal degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), brain-specific oxysterol catalyzed CYP46A1, elevated cerebrospinal fluid PD patients. Herein, we show levels CYP46A1 24-OHC patients increase with age mouse model. Overexpression intensifies pathology, whereas genetic removal attenuates neurotoxicity brain. supplementation exogenous exacerbates mitochondrial dysfunction induced fibrils. Intracerebral injection enhances spread neurodegeneration via X-box binding protein 1 (XBP1) lymphocyte-activation gene 3 (LAG3) levels. Thus, promote XBP1–LAG3 axis. Strategies aimed at inhibiting CYP46A1-24-OHC axis LAG3 could hold promise as disease-modifying therapies

Language: Английский

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Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation

Journal of Xenobiotics, Journal Year: 2025, Volume and Issue: 15(2), P. 44 - 44

Published: March 14, 2025

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and progression of neurodegenerative diseases. The brain’s complex architecture, composed interconnected cell types receptors, drives unique neuronal signaling pathways, modulates enzyme functions, leads to distinct CYP gene expression regulation patterns compared liver. Despite their relatively low levels expression, CYPs exert significant influence on responses, neurotoxin susceptibility, behavior, neurological disease risk. These are essential maintaining homeostasis, mediating cholesterol turnover, synthesizing metabolizing neurochemicals, neurosteroids, neurotransmitters. Moreover, they key participants oxidative stress neuroprotection, inflammation. In addition roles psychotropic drugs, substances abuse, endogenous compounds, impact efficacy, safety, resistance, underscoring importance beyond traditional metabolism. Their involvement critical physiological processes also links them onset Understanding cerebral is vital advancing neuroprotective strategies, personalizing treatments disorders, developing CNS-targeting therapeutics. This review explores emerging enzymes, particularly those within CYP1–3 CYP46 families, highlighting functional diversity pathological consequences dysregulation health. It examines potential CYP-based biomarkers improve diagnosis treatment offering new avenues therapeutic innovation.

Language: Английский

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Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration

iScience, Journal Year: 2024, Volume and Issue: 27(4), P. 109454 - 109454

Published: March 8, 2024

Neuropathology is often mediated by interactions between neurons and glia that cannot be modeled monocultures. However, cocultures are difficult to use analyze for high-content screening. Here, we perform compound screening using primary neuron-glia cultures model inflammatory neurodegeneration, live-cell stains, automated classification of neurons, astrocytes or microglia open-source software. Out 227 compounds with known bioactivities, 29 protected against lipopolysaccharide-induced neuronal loss, including drugs affecting adrenergic, steroid, MAP kinase signaling. The screen also identified physiological compounds, such as noradrenaline progesterone, neurotoxic a TLR7 agonist, induced microglial proliferation. Most used here have not been tested in coculture neurodegeneration assay previously. Thus, combining complex cellular disease image analysis allows identification important biology, well potential targets treatment.

Language: Английский

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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

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SNPs in cytochrome P450 genes decide on the fate of individuals with genetic predisposition to Parkinson’s disease

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 4, 2023

Parkinson’s disease (PD) is one of the most frequent neurological diseases affecting millions people worldwide. While majority PD cases are unknown origin (idiopathic), about 5%–10% familial and linked to mutations in different known genes. However, there also with a genetic predisposition who do not develop disease. To elucidate factors leading manifestation we compared occurrence single nucleotide polymorphisms (SNPs) various cytochrome P450 (P450) genes suffering from (GPD) that people, genetically predisposed, but show no symptoms (GUN). We used PPMI (Parkinson’s Progression Markers Initiative) database gene sequences all 57 P450s as well their three redox partners. Corresponding odds ratios (OR) confidence intervals (CI) were calculated assess incidence SNPs two groups individuals consequently relation PD. identified for first time significantly (up 10fold!) over- or under-represented GPD patients GUN. OR > 5 found 10 being involved eicosanoid, vitamin A D metabolism cholesterol degradation pointing an important role endogenous clinical symptoms. Moreover, 12 belonging substrate classes POR have (OR < 0.2) GUN, indicating protective those corresponding regarding advancement. best our knowledge data demonstrate association between other genes, shown here partner POR, which promote Our results thus shed light onto pathogenesis PD, especially switch GUN might further help advance novel strategies preventing development progression

Language: Английский

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Personalized Medicine Approach to Proteomics and Metabolomics of Cytochrome P450 Enzymes: A Narrative Review

European Journal of Drug Metabolism and Pharmacokinetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 13, 2024

Language: Английский

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