Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation

Valenza, Marta; Carroll, Jeffrey B.; Leoni, Valerio; Bertram, Lisa; Björkhem, Ingemar; Singaraja, Roshni R.; Donato, Stefano Di; Lütjohann, Dieter; Hayden, Michael R.; Cattaneo, Elena

doi:10.1093/hmg/ddm170

Cited by 111 publications

(113 citation statements)

References 43 publications

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“…17 HTT-depleted astrocytes displayed the same reduction in apoE level as in Q111/7 (Figure 1c), supporting the hypothesis that normal HTT has a role in cholesterol synthesis. 18 Furthermore, primary astrocytes from a transgenic HD mouse model (R6/2; Supplementary Figure 1f) secreted lower apoE levels compared with primary wt astrocytes ( Figure 1d). Quantitative assays confirmed that concentrations of apoE ( Figure 1e) and cholesterol ( Figure 1f) were significantly reduced in conditioned media from Q140/7 astrocytes and from primary R6/2 astrocytes compared with their respective controls.…”

Section: Resultsmentioning

confidence: 95%

“…49 Similarly, cholesterol biosynthesis disruption in HD animal models and patients occurs before the onset of motor defect. 9,10,18,50 Additionally, synaptosomes carry suboptimal levels of sterols in early R6/2 model. 8 Here, we showed that a non-cell autonomous cholesterol-handling defect in astrocytes affects cholesterol shuttling between astrocytes and neurons, which has a reversible detrimental effect on synaptic-related parameters in HD neurons.…”

Section: Discussionmentioning

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: 95%

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…The mean body weight of R6/1 mice did not increase after 16 weeks of age in males, and 19 weeks in females. Prior to weight loss (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) weeks) the rate of weight gain was significantly less in female R6/1 mice compared to WT (p = 0.00012). No significant difference in the rate of weight gain was detected between male R6/1 and WT mice in the 6-16 week period.…”

Section: Weight Loss In R6/1 Mousementioning

confidence: 98%

“…Although the rate of cholesterol synthesis in peripheral tissues can be estimated by plasma levels of cholesterol synthetic precursors (lathosterol and lanosterol), these do not reflect central nervous system (CNS) cholesterol synthesis. Direct measurement of sterol precursor levels in brain tissue is therefore necessary to monitor the cholesterol synthetic pathway [7,8,17].…”

Section: Introductionmentioning

confidence: 99%

“…Perturbed cholesterol synthetic and metabolic pathways have been previously reported in HD mouse and cell models [5][6][7]17]. Due to the complexity of the cholesterol synthetic pathway, previous studies have measured some of the major brain synthetic sterol intermediates and metabolites, but the full extent of potential sterol alterations that may occur in different brain regions has not been fully examined.…”

Section: Introductionmentioning

confidence: 99%

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Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Kreilaus

Spiro

Hannan

et al. 2015

JHD

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. (2015). Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington's disease: a targeted GC-MS/MS sterol analysis. Journal of Huntington's Disease, 4 (4), 305-318.Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington' s disease: a targeted GC-MS/MS sterol analysis AbstractBackground:Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood. Objective:This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease. We also aimed to characterise the progression of the physical phenotype in these mice. Methods:GC-MS/MS was used to quantify a broad range of sterols in the striatum and cortex of R6/1 and wild type mice at 6, 12, 20, 24 and 28 weeks of age. Motor dysfunction was assessed over 28 weeks using the RotaRod and the hind-paw clasping tests. Results:24(S)-Hydroxycholesterol and 27-hydroxycholesterol were the major cholesterol metabolites that significantly changed in R6/1 mice. These changes were specifically localised to the striatum and were detected at the end stages of the disease. Cholesterol synthetic precursors (lathosterol and lanosterol) were significantly reduced in the cortex and striatum by 6 weeks of age, prior to the onset of motor dysfunction, as well as the cognitive and affective abnormalities previously reported. Elevated levels of desmosterol, a substrate of delta(24)-sterol reductase (DHCR24), were also detected in R6/1 mice at the end time-point. Female R6/1 mice exhibited a milder weight loss and hind paw clasping phenotype compared to male R6/1 mice, however, no difference in the brain sterol profile was detected between sexes. Conclusion:Several steps in cholesterol biosynthetic and metabolic pathways are differentially altered in the R6/1 mouse brain as the disease progresses and this is most severe in the striatum. This provides further insights into early molecular mediators of HD onset and disease progression and identifies candidate molecular targets for novel therapeutic approaches.

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Huntington's disease, calcium, and mitochondria

2011

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Huntington's disease (HD) is caused by a mutation that increases the number of CAG repeats in the gene encoding for the protein Huntingtin (Htt). The mutation results in the pathological expansion of the polyQ stretch that is normally present within the N-terminal region of Htt. Even if Htt is ubiquitously expressed in tissues, the changes in the protein finally result in the clinical manifestation of motor and cognitive impairments observed in HD patients. The molecular ethiology of the disease is obscure: a number of cellular and animal models are used as essential tools in experimental approaches aimed at understanding it. Biochemical changes have been described that correlate with the malfunction of HD neurons (primarily in the striatum): consensus is gradually emerging that the dyshomeostasis of Ca(2+) and/or mitochondria stress are important factors in the linkage of the Htt mutation to the onset and progression of the disease. Here, we present a succint overview of the changes of Htt, of its possible effect on the transcription of critical genes and of its causative role in the disturbance of the neuronal Ca(2+) homeostasis. Particular emphasis will be placed on the role of mitochondria as key player in the molecular pathogenesis of the disease.

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Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation

Cited by 111 publications

References 43 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

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Huntington's disease, calcium, and mitochondria

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