Malformation syndromes caused by disorders of cholesterol synthesis

Porter, Forbes D.; Herman, Gail E.

doi:10.1194/jlr.r009548

Cited by 407 publications

(452 citation statements)

References 331 publications

(405 reference statements)

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“…Similar results were obtained with four other independent differentiations. (j) Neurite outgrowth quantification in Q140/7 neurons under glial-free conditions (vehicle) or in the presence of increasing doses of cholesterol (3,5,7,10,12, and 20 μg/ml) immunostained for MAP2. The graph shows the mean (a.u.)…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels.…”

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confidence: 99%

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Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

et al. 2014

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In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyteneuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD. Huntington's disease (HD) is an adult-onset neurodegenerative disorder characterized by cell loss mainly in the striatum and cortex. Its pathophysiology is linked to an expanded CAG repeat in the IT-15 gene, which leads to an elongated polyQ tract in huntingtin (HTT) protein. No disease-modifying treatment is available for HD and novel pathophysiological insights and therapeutic strategies are needed. 1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC). 9,10 However, it remains unclear how reduced brain cholesterol would become pathological for HD neurons.In adulthood, astrocytes produce cholesterol, which is secreted as a complex with apolipoprotein (apo) E lipoproteins and delivered to neurons. 11,12 Mutant HTT is expressed in glial cells, 13,14 and transgenic mice overexpressing mutant HTT in astrocytes show age-dependent neurological symptoms. 15,16 Additionally, primary astrocytes overexpressing full-length human mutant HTT show reduced mRNA levels of cholesterol biosynthetic genes, along with impaired cellular production and secretion of apoE. 8 Here we employed molecular and cellular tools to test the impact of cholesterol perturbation between astrocytes and neur...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

et al. 2014

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“…CHOL homeostasis of the mammalian cells is strictly regulated by complex mechanisms [51]. In the last decades, numerous malformation syndromes have been associated with the inborn error of the CHOL synthesis (reviewed in [46]). The link between reduced CHOL synthesis and a serious health condition was described first for the Smith-LemliOpitz syndrome (SLOS) [29,59,65].…”

Section: Introductionmentioning

confidence: 99%

“…The link between reduced CHOL synthesis and a serious health condition was described first for the Smith-LemliOpitz syndrome (SLOS) [29,59,65]. The SLOS phenotypic spectrum is very broad, ranging from a mild disorder with behavioral and learning problems to a lethal malformation syndrome (incidence of SLOS is 1 in 39,000 births [17]) [45,46]. The disease is characterized by the constellation of severe birth defects affecting multiple organ systems (central nervous system, cardiac, pulmonoray, gastrointestinal).…”

Section: Introductionmentioning

confidence: 99%

“…Growth failure and feeding problems are also common in SLOS. Moreover, many SLOS infants have behaviour problems (autism, hyperactivity, self-injures behavior) [45,46]. Irons and his colleagues showed that the SLOS is caused by the deficiency of 7-dehyrocholesterol-reductase (DHCR7), which catalyzes the last step in the CHOL biosynthetic pathway [29].…”

Section: Introductionmentioning

confidence: 99%

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7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

Balajthy

Somodi

Pethő

et al. 2016

Pflugers Arch - Eur J Physiol

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In vitro manipulation of membrane sterol level affects the regulation of ion channels and consequently certain cellular functions; however, a comprehensive study that confirms the pathophysiological significance of these results is missing. The malfunction of 7-dehydrocholesterol (7DHC) reductase in Smith-Lemli-Opitz syndrome (SLOS) leads to the elevation of the 7-dehydrocholesterol level in the plasma membrane. T lymphocytes were isolated from SLOS patients to assess the effect of the in vivo altered membrane sterol composition on the operation of the voltage-gated Kv1.3 channel and the ion channel-dependent mitogenic responses. We found that the kinetic and equilibrium parameters of Kv1.3 activation changed in SLOS cells. Identical changes in Kv1.3 operation were observed when control/healthy T cells were loaded with 7DHC. Removal of the putative sterol binding sites on Kv1.3 resulted in a phenotype that was not influenced by the elevation in membrane sterol level. Functional assays exhibited impaired activation and proliferation rate of T cells probably partially due to the modified Kv1.3 operation. We concluded that the altered membrane sterol composition hindered the operation of Kv1.3 as well as the ion channel-controlled T cell functions.

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Membrane Cholesterol: Implications in Receptor Function

Shrivastava

Chattopadhyay

2012

Cholesterol Regulation of Ion Channels and Receptors

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Malformation syndromes caused by disorders of cholesterol synthesis

Cited by 407 publications

References 331 publications

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

Membrane Cholesterol: Implications in Receptor Function

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