Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Fukui, Kenji; Ferris, Heather A.; Kahn, C. Ronald

doi:10.1074/jbc.m115.664367

Cited by 48 publications

(40 citation statements)

References 49 publications

(59 reference statements)

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“…Given the many roles of cholesterol in the CNS, it is clear that any disruption in the cholesterol supply to neurons can likely contribute to neurodysfunction. In agreement with human and animal studies, in vitro studies demonstrate that depletion of cholesterol has deleterious effects on neuronal function (Frank et al 2008;Fukui, Ferris, & Kahn, 2016;Thiele, Hannah, Fahrenholz, & Huttner, 2000;Valenza et al 2015). Taken together, this reveals a potential convergence point for cocaine use and HIV-1 Tat to accelerate neurocognitive impairment.…”

Section: Discussionsupporting

confidence: 71%

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cotto

Natarajaseenivasan

Ferrero

et al. 2018

Glia

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Cholesterol synthesis and clearance by astrocytes are tightly regulated to maintain constant levels within the brain. In this context, liver X receptors (LXRs) are the master regulators of cholesterol homeostasis in the central nervous system (CNS). Increasing levels of cholesterol in astrocytes trigger LXR activation leading to the transcription of target genes involved in cholesterol trafficking and efflux, including apolipoprotein E, cytochrome P450 enzymes, sterol regulatory binding protein, and several ATP-binding cassette transporter proteins. The disturbance of LXR signaling in the brain can lead to significant dysfunctions in cholesterol homeostasis, and disruptions in this pathway have been implicated in numerous neurological diseases including Alzheimer's disease and Huntington's disease. HIV infection of the CNS in combination with cocaine use is associated with astrocyte and neuronal energy deficit and damage. We propose that dysregulation in CNS cholesterol metabolism may be involved in the progression of HIV-associated neurocognitive disorders (HAND) and in cocaine-mediated neurocognitive impairments. We hypothesize that exposure of astrocytes to cocaine and the HIV protein Tat will disrupt LXR signaling. Alterations in these pathways will in turn, affect cholesterol bioavailability for neurons. Our data show that exposure of astrocytes to cocaine and HIV-Tat significantly decreases LXRβ levels, downstream signaling and bioavailability of cholesterol. Taken together, these data uncover novel alterations in a bioenergetic pathway in astrocytes exposed to cocaine and the HIV protein Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine user individuals.

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Section: Discussionsupporting

confidence: 71%

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cotto

Natarajaseenivasan

Ferrero

et al. 2018

Glia

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“…In many cases, recruitment of the receptor into lipid rafts following activation or receptor activation within the raft itself is critical for the type and duration of downstream signaling and can lead to dramatically different cellular outcomes if the receptor is activated elsewhere. Additionally, disruption of lipid rafts through cholesterol depletion or other destabilizing agents has inhibitory effects, especially on RTKmediated signals, most notably the PI3K/Akt and ERK pathways in neurons (Fukui et al, 2015). These observations highlight the importance of plasma membrane compartmentalization and lipid raft integrity in maintaining signaling pathways important for cellular growth and survival.…”

Section: Influence Of Membrane Architecture On Neuronal Signalingmentioning

confidence: 99%

How membrane dysfunction influences neuronal survival pathways in sphingolipid storage disorders

Sural-Fehr

Bongarzone

2016

J of Neuroscience Research

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Sphingolipidoses are a class of inherited diseases that result from the toxic accumulation of undigested sphingolipids in lysosomes and other cellular membranes. Sphingolipids are particularly enriched in cells of the nervous system, and their excessive accumulation during disease has a significant impact on the nervous system. Neuronal dysfunction followed by neurological compromise is a common feature in many of these diseases, however the underlying mechanisms that cause vulnerability of neurons are not fully understood. The plasma membrane plays a critical role in regulating cellular survival pathways, and its dysfunction has been implicated in neuronal failure in various adult onset neuropathies. In the context of sphingolipidoses, we hypothesized that the gradual accumulation of undigested lipids in plasma membranes would cause local disruptions in lipid raft domains, leading to deregulation of multiple signaling pathways important for neuronal survival and function. We propose that defects in downstream signaling as a result of membrane dysfunction is a common mechanism underlying neuronal vulnerability in sphingolipid storage disorders with neurological compromise.

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“…Its biosynthesis occurs through a stepwise cascade involving several enzymes under transcriptional regulation by sterol regulatory element binding protein 2 (SREBP2) transcription factor (3). In the adult brain, a small amount of cholesterol continues to be synthesized locally, where it regulates multiple processes including synapse formation and maintenance, synaptic vesicle (SV) recycling, and optimal release of neurotransmitters for downstream intracellular signaling pathways (4)(5)(6)(7). Consequently, dysregulation of brain cholesterol homeostasis is linked to several chronic neurological and neurodegenerative diseases (8,9).…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent and disease-modifying effects of striatal infusion of cholesterol in Huntington’s disease

Birolini

Valenza

Paolo

et al. 2020

Preprint

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A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD).Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre-symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol-loaded brain-permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini-pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and ratecontrolled manner. All tested doses prevented cognitive decline, while amelioration of disease-related motor defects was dose-dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose-dependent, disease-modifying effect and may be therapeutically relevant in HD.

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Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Cited by 48 publications

References 49 publications

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients

How membrane dysfunction influences neuronal survival pathways in sphingolipid storage disorders

Dose-dependent and disease-modifying effects of striatal infusion of cholesterol in Huntington’s disease

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