Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: July 8, 2021

Cholesterol, an essential component of the brain, and its local metabolism are involved in many neurodegenerative diseases. The blood-brain barrier is impermeable to cholesterol; hence, cholesterol homeostasis central nervous system represents a balance between situ biosynthesis elimination. Cytochrome P450 46A1 (CYP46A1), system-specific enzyme, converts 24-hydroxycholesterol, which can freely cross be degraded liver. By dual action initiating efflux activating synthesis pathway, CYP46A1 key enzyme that ensures brain turnover. In humans mouse models, activity altered Alzheimer’s Huntington’s diseases, spinocerebellar ataxias, glioblastoma, autism spectrum disorders. modulations mitigate manifestations Alzheimer’s, Huntington’s, Nieman-Pick type C, Machao-Joseph (spinocerebellar ataxia 3) diseases as well amyotrophic lateral sclerosis, epilepsy, prion infection. Animal studies revealed effects not limited maintenance but also involve critical cellular pathways, like gene transcription, endocytosis, misfolded protein clearance, vesicular transport, synaptic transmission. How exert control such functions pressing question under investigation. potential therapeutic role CYP46A1, demonstrated numerous models disorders, currently being evaluated early clinical trials. This review summarizes past 70 years research has led identification powerful targets for severe pathologies CNS.

Language: Английский

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Role of Brain Liver X Receptor in Parkinson’s Disease: Hidden Treasure and Emerging Opportunities

Molecular Neurobiology, Journal Year: 2023, Volume and Issue: 61(1), P. 341 - 357

Published: Aug. 22, 2023

Abstract Parkinson’s disease (PD) is a neurodegenerative due to the degeneration of dopaminergic neurons (DNs) in substantia nigra (SN). The liver X receptor (LXR) involved different diseases. Therefore, objective present review was clarify possible role LXR PD neuropathology. LXRs are most common nuclear receptors transcription factors that regulate cholesterol metabolism and have pleiotropic effects, including anti-inflammatory effects reducing intracellular accumulation. highly expressed adult brain act as endogenous sensors for cholesterol. neuroprotective against development neuroinflammation diseases by inhibiting expression pro-inflammatory cytokines. play an essential mitigating neuropathology inflammatory signaling pathways, neuroinflammation, oxidative stress, mitochondrial dysfunction, enhancement BDNF signaling. In conclusion, LXRs, through regulating homeostasis, may be effectual PD. Also, inhibition node-like pyrin 3 (NLRP3) inflammasome factor kappa B (NF-κB) could effectively prevent Taken together, crucial associated DNs.

Language: Английский

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25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

Biochemistry (Moscow), Journal Year: 2022, Volume and Issue: 87(6), P. 524 - 537

Published: June 1, 2022

Language: Английский

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The potential role of cholesterol in Parkinson’s disease neuropathology: perpetrator or victim

Neurological Sciences, Journal Year: 2023, Volume and Issue: 44(11), P. 3781 - 3794

Published: July 10, 2023

Language: Английский

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Glutamate at the Vertebrate Neuromuscular Junction: From Modulation to Neurotransmission

Cells, Journal Year: 2019, Volume and Issue: 8(9), P. 996 - 996

Published: Aug. 28, 2019

Although acetylcholine is the major neurotransmitter operating at skeletal neuromuscular junction of many invertebrates and vertebrates, glutamate participates in modulating cholinergic transmission plastic changes last. Presynaptic terminals junctions contain release that contribute to regulation synaptic neurotransmission through its interaction with pre- post-synaptic receptors activating downstream signaling pathways tune efficacy plasticity. During vertebrate development, chemical nature can be experimentally shifted from other mediators (including glutamate) modulation calcium dynamics motoneurons and, when changes, muscle fiber expresses assembles new match mediator. Finally, adult rodents, by diverting descending spinal glutamatergic axons a denervated muscle, functional reinnervation achieved formation use as express ionotropic markers central synapses. Here, we summarize past recent experimental evidences support role mediator synapse between motor nerve ending fiber, focusing on molecules are present activated junction.

Language: Английский

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Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 9022 - 9022

Published: May 19, 2023

Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations RNA-binding protein FUS are one the common genetic reasons ALS accompanied by a ‘dying back’ type degeneration. Using fluorescent approaches microelectrode recordings, early structural functional alterations in diaphragm neuromuscular junctions (NMJs) were studied mutant mice at pre-onset stage. Lipid peroxidation decreased staining with lipid raft marker found mice. Despite preservation end-plate structure, immunolabeling revealed an increase levels presynaptic proteins, SNAP-25 synapsin 1. The latter can restrain Ca2+-dependent synaptic vesicle mobilization. Indeed, neurotransmitter release upon intense nerve stimulation its recovery after tetanus compensatory endocytosis markedly depressed There was trend to attenuation axonal [Ca2+]in 20 Hz. However, no changes intraterminal Ca2+ transient response low frequency or quantal content synchrony external detected. At later stage, shrinking fragmentation end plates together decrease expression disturbance timing occurred. Overall, suppression exo–endocytosis activity probably due membrane properties, 1 kinetics could be sign nascent NMJ pathology, which leads contact disorganization.

Language: Английский

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Effects of membrane cholesterol-targeting chemicals on skeletal muscle contractions evoked by direct and indirect stimulation

Journal of Muscle Research and Cell Motility, Journal Year: 2024, Volume and Issue: 45(4), P. 221 - 231

Published: June 21, 2024

Language: Английский

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Decremental response in patients with amyotrophic lateral sclerosis during repetitive nerve stimulation and its relationships with impaired homeostasis

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 7, 2025

Previous studies have suggested that neuromuscular junction (NMJ) denervation plays a critical role in amyotrophic lateral sclerosis (ALS). Repetitive nerve stimulation (RNS) has been used as technique to test transmission, but the sensitivity and stability of its parameters not investigated patients with ALS. In addition, impact impaired homeostasis on NMJ ALS remains unclear. A total 421 were enrolled. Data their clinical, biochemical electrophysiological indicators divided into training set (collected from June 2019 2022) July 2022 2023). The coefficient variation (CV) was assess extent variability. Stepwise regression independent variable selection model building. ALS, area decrement had higher rate abnormal result lower CV than amplitude decrement. No significant difference found when first compound muscle action potential (CMAP) compared either fourth or fifth one. Moreover, multivariate analysis suggests high-density lipoprotein cholesterol (HDL-C) greatest decremental response, followed by serum uric acid (UA) forced vital capacity (FVC). Females larger range males. During RNS test, assessing significantly enhances our ability detect impairment transmission Independent factors contributing response need be considered drug development clinical trials targeting

Language: Английский

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25-Hydroxycholesterol as a negative regulator of diaphragm muscle contractions via estrogen receptor and Ca2+ -dependent pathway

Histochemistry and Cell Biology, Journal Year: 2025, Volume and Issue: 163(1)

Published: April 3, 2025

Language: Английский

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Cholesterol metabolism and neuroinflammatory changes in a non-human primate spinal nerve ligation model

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 3, 2025

Language: Английский

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