Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington’s disease

Valenza, Marta; Leoni, Valerio; Tarditi, Alessia; Mariotti, Caterina; Björkhem, Ingemar; Donato, Stefano Di; Cattaneo, Elena

doi:10.1016/j.nbd.2007.07.004

Cited by 109 publications

(133 citation statements)

References 48 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…AD and HD) (Cutler et al, 2004;Valenza et al, 2007). The aim of the present work was to explore the effect of MβCD-induced cholesterol depletion on synaptic transmission and synaptic plasticity in the CA1 pyramidal cell layer of rat hippocampal slices, thus elucidating how altered lipid homeostasis might mediate pathogenic mechanisms responsible for neurodegeneration.…”

Section: Discussionmentioning

confidence: 98%

“…Although doubts about the nature of these microdomains still remain (Shaw, 2006), the existence of "lipid rafts" and the proteins bound to them are generally considered essential for a broad range of activities in the nervous system, including neuronal excitability and synaptic transmission (Tsui-Pierchala et al, 2002). It is not surprising that several human diseases of the nervous system, such as Alzheimer's (AD), Huntington's (HD), Niemann Pick's and prion's Diseases (Vance, 2006;Valenza et al, 2007;Cutler et al, 2004;Hooper, 2005), involve an impairment of lipid metabolism and transport. It has been proposed that the neurotoxic protein, β-amyloid is produced in lipid rafts after hydrolysis of the amyloid precursor protein (APP) by preseniline (Cordy et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Since brain cholesterol levels increase in AD (Cutler et al, 2004), and hypercholesterolemia is an early risk factor for its development (Pappolla et al, 2003;Lane and Farlow, 2005), cholesterol-lowering drugs might be a potential treatment for this disease (Wolozin et al, 2000). Recently in the R6/2 mice, a model of HD, it has been reported that cholesterol biosynthesis pathway is reduced in brain (Valenza et al, 2007) showing abnormalities in synaptic plasticity (Picconi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus

Frank

Rufini

Tancredi

et al. 2008

Experimental Neurology

115

View full text Add to dashboard Cite

Several neurodegenerative disorders are associated with impaired cholesterol homeostasis in the nervous system where cholesterol is known to play a role in modulating synaptic activity and stabilizing membrane microdomains. In the present report, we investigated the effects of methyl-β-cyclodextrin-induced cholesterol depletion on synaptic transmission and on the expression of 1) paired-pulse facilitation (PPF); 2) paired-pulse inhibition (PPI) and 3) long-term potentiation (LTP) in the CA1 hippocampal region. Results demonstrated that cyclodextrin strongly reduced synaptic transmission and blocked the expression of LTP, but did not affect PPF and PPI. The role of glutamatergic and GABAergic receptors in these cholesterol depletion-mediated effects was evaluated pharmacologically. Data indicate that, in cholesterol depleted neurons, modulation of synaptic transmission and synaptic plasticity phenomena are sustained by AMPA-, kainate-and NMDA-receptors but not by GABA-receptors. The involvement of AMPA-and kainate-receptors was confirmed by fluorimetric analysis of intracellular calcium concentrations in hippocampal cell cultures. These data suggest that modulation of receptor activity by manipulation of membrane lipids is a possible therapeutic strategy in neurodegenerative disease.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus

Frank

Rufini

Tancredi

et al. 2008

Experimental Neurology

115

View full text Add to dashboard Cite

show abstract

“…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%

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

et al. 2014

View full text Add to dashboard Cite

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...

show abstract

“…These include the dysregulation of glutamatergic and dopaminergic signaling (Zeron et al, 2002;Cepeda et al, 2003;Cummings et al, 2006;Johnson et al, 2006;Tang et al, 2007), the dysfunction of calcium homeostasis (Panov et al, 2002;Brustovetsky et al, 2005;Tang et al, 2005), metabolic abnormalities (Weydt et al, 2006;Lee et al, 2007;Valenza et al, 2007;van der Burg et al, 2008), and decreases in brain-derived neurotrophic factor (Zuccato et al, 2003;Gauthier et al, 2004). These events can also lead to downstream changes in gene expression (Lee et al, 2007;Strand et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry

Runne¹,

Régulier²,

Kuhn³

et al. 2008

J. Neurosci.

View full text Add to dashboard Cite

Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington’s disease

Cited by 109 publications

References 48 publications

Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus

Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus

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

Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry

Contact Info

Product

Resources

About