Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Апрель 28, 2022

Once believed to be part of the nervenkitt or “nerve glue” network in central nervous system (CNS), oligodendroglial cells now have established roles key neurological functions such as myelination, neuroprotection, and motor learning. More recently, oligodendroglia has become subject intense investigations aimed at understanding contributions its energetics CNS physiology pathology. In this review, we discuss current metabolism regulating stages development health, role providing energy neighboring neurons, well how alterations bioenergetics contribute disease states. Importantly, highlight certain inputs can regulate metabolism, including extrinsic intrinsic mediators cellular signaling, pharmacological compounds, even dietary interventions. Lastly, emerging studies discovering therapeutic potential targeting components within bioenergetic pathways.

Язык: Английский

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The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

Acta Neuropathologica Communications, Год журнала: 2022, Номер 10(1)

Опубликована: Март 16, 2022

Previous studies show that 3β-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In cholesterol synthetic metabolism, DHCR24 is known as heavily key synthetase synthesis. Moreover, mutations gene result inhibition enzymatic activity DHCR24, causing deficiency and desmosterol accumulation. Furthermore, vitro also demonstrated knockdown lead to synthesis, decrease plasma membrane intracellular level. Obviously, could play crucial role maintaining homeostasis via control Over past two decades, accumulating data suggests downregulated by major risk factors for AD, suggesting potential link between downregulation pathogenesis. Thus, loss seems be induced possible causative AD. According previous our study, we further found reduced level compartments obviously was involved β-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal lipid raft disorganization are linked neuropathological impairments which associated with Therefore, based on research suppose deficiency/loss might pathogenesis

Язык: Английский

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25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

Biochemistry (Moscow), Год журнала: 2022, Номер 87(6), С. 524 - 537

Опубликована: Июнь 1, 2022

Язык: Английский

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DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice

Acta Neuropathologica Communications, Год журнала: 2023, Номер 11(1)

Опубликована: Июнь 21, 2023

Abstract Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer’s disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls homeostasis, which was found to be downregulated in AD vulnerable regions and involved AD-related pathological activities. However, DHCR24 as potential therapeutic target for remains identified. In present study, we demonstrated role by employing delivery adeno-associated virus carrying gene into hippocampus 5xFAD mice. Here, mice had lower levels expression, loss alleviated overexpression. Surprisingly, cognitive impairment significantly reversed after DHCR24-based therapy. Moreover, revealed knock-in successfully prevented or pathology mice, including amyloid-β deposition, synaptic injuries, autophagy, reactive astrocytosis, microglial phagocytosis apoptosis. conclusion, our results firstly value DHCR24-mediated regulation level promising treatment AD.

Язык: Английский

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Pharmacological Regulation of Endoplasmic Reticulum Structure and Calcium Dynamics: Importance for Neurodegenerative Diseases

Pharmacological Reviews, Год журнала: 2023, Номер 75(5), С. 959 - 978

Опубликована: Май 1, 2023

The endoplasmic reticulum (ER) is the largest organelle of cell, composed a continuous network sheets and tubules, involved in protein, calcium (Ca²⁺) lipid homeostasis. In neurons, ER extends throughout both somal axodendritic compartments, highly important for neuronal functions. A third proteome secreted membrane-bound proteins, are processed within lumen most these proteins vital activity. brain itself high content many structural lipids produced, part, by ER. Cholesterol steroid synthesis strictly regulated blood-brain barrier protected cells. Ca²⁺ level low cytosolic concentration needed Ca²⁺-based intracellular signaling, also synaptic signaling waves, as well preparing correct folding presence concentrations to cope with extracellular milieu. Particularly, Ca²⁺ is controlled areas proper neurito- synaptogenesis plasticity remodeling. this review, we cover physiological functions discuss it context common neurodegenerative diseases focusing on pharmacological regulation Ca²⁺. Furthermore, postulate that heterogeneity ER, its protein capacity ensuring crucial factor aging selective vulnerability neurons various diseases. Significance Statement regulators promising therapeutic targets degenerative which efficacious drug therapies do not exist. use probes targeting maintenance restoration can provide homeostasis, e.g. complex plasma membrane signalling receptors slow down degeneration process neurons.

Язык: Английский

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Lipid Rafts: The Maestros of Normal Brain Development

Biomolecules, Год журнала: 2024, Номер 14(3), С. 362 - 362

Опубликована: Март 18, 2024

Lipid rafts, specialised microdomains within cell membranes, play a central role in orchestrating various aspects of neurodevelopment, ranging from neural differentiation to the formation functional neuronal networks. This review focuses on multifaceted involvement lipid rafts key neurodevelopmental processes, including differentiation, synaptogenesis and myelination. Through spatial organisation signalling components, facilitate precise events that determine fate during embryonic development adulthood. The evolutionary conservation underscores their fundamental importance for structural complexity nervous system all species. Furthermore, there is increasing evidence environmental factors can modulate composition function influence processes. Understanding intricate interplay between neurodevelopment not only sheds light mechanisms governing brain but also has implications therapeutic strategies aimed at cultivating networks addressing disorders.

Язык: Английский

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Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury

ACS Chemical Neuroscience, Год журнала: 2018, Номер 10(3), С. 1595 - 1602

Опубликована: Ноя. 13, 2018

Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging breast cancer treatment of Alzheimer's disease schizophrenia. These promising applications coupled our previous observation that σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes improves cognition wild-type mice suggests modulating may also have benefits other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, report DKR-1677, a novel derivative increased affinity selectivity σ2R/Tmem97 (Ki = 5.1 nM), is after blast-induced controlled cortical impact (CCI) TBI mice. Specifically, discovered DKR-1677 decreases axonal degeneration enhances survival neurons oligodendrocytes CCI injury. Furthermore, preserves Morris water maze blast TBI. Our results support an increasingly broad role modulation neuroprotection suggest new approach treating patients suffering from

Язык: Английский

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Cholesterol in the Pathogenesis of Alzheimer’s, Parkinson’s Diseases and Autism: Link to Synaptic Dysfunction

Acta Naturae, Год журнала: 2017, Номер 9(1), С. 26 - 37

Опубликована: Март 15, 2017

In our previous review, we described brain cholesterol metabolism in control conditions and the case of some rare neurological pathologies linked to defects genes which are directly involved synthesis and/or traffic cholesterol. Here, have analyzed disruptions homeostasis widespread neurodegenerative diseases (Alzheimers Parkinsons diseases) autism spectrum disorders. We particularly focused on synaptic dysfunctions that could arise from changes both membrane availability oxysterol production. Notably, alterations neurotransmission occur early stages these polymorphism associated with communication affects risk onset severity diseases. addition, pharmacological genetic manipulations animal models frequently marked effects progression Thus, development Alzheimers, disorders may be partially an imbalance leads levels that, turn, modulates key steps transmission.

Язык: Английский

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Cholesterol and the Safety Factor for Neuromuscular Transmission

International Journal of Molecular Sciences, Год журнала: 2019, Номер 20(5), С. 1046 - 1046

Опубликована: Фев. 28, 2019

A present review is devoted to the analysis of literature data and results own research. Skeletal muscle neuromuscular junction specialized trigger striated fiber contraction in response motor neuron activity. The safety factor at strongly depends on a variety pre- postsynaptic factors. focuses crucial role membrane cholesterol maintain high efficiency transmission. Cholesterol metabolism junction, its synaptic vesicle cycle neurotransmitter release, endplate electrogenesis, as well contribution synaptogenesis, integrity, disorders are discussed.

Язык: Английский

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Membrane lipid rafts are disturbed in the response of rat skeletal muscle to short-term disuse

AJP Cell Physiology, Год журнала: 2017, Номер 312(5), С. C627 - C637

Опубликована: Март 9, 2017

Marked loss of skeletal muscle mass occurs under various conditions disuse, but the molecular and cellular mechanisms leading to atrophy are not completely understood. We investigate early events that might play a role in remodeling during mechanical unloading (disuse). The effects acute (6–12 h) hindlimb suspension on soleus muscles from adult rats were examined. integrity plasma membrane lipid rafts was tested utilizing cholera toxin B subunit or fluorescent sterols. In addition, resting intracellular Ca 2+ level analyzed. Acute disuse disturbed lipid-ordered phase throughout sarcolemma more pronounced junctional regions. Ouabain (1 µM), which specifically inhibits Na-K-ATPase α2 isozyme rodent muscles, produced similar raft changes control ineffective suspended showed an initial activity. Lipid able recover with cholesterol supplementation, suggesting disturbance results loss. Repetitive nerve stimulation also restores rafts, region. Disuse locally lowered concentration only near neuromuscular junction fibers. Our provide evidence suggest ordering strongly depends motor input may involve interactions Na-K-ATPase. disturbance, accompanied by dysregulation, is among earliest induced disuse.

Язык: Английский

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