CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease

Boussicault, Lydie; Alves, Sandro; Lamazière, Antonin; Planques, Anabelle; Heck, Nicolas; Moumné, Lara; Despres, Gaëtan; Bolte, Susanne; Hu, Amélie; Pagès, Christiane; Galvan, Laurie; Piguet, Françoise; Aubourg, Patrick; Cartier, Nathalie; Caboche, Jocelyne; Bétuing, Sandrine

doi:10.1093/brain/awv384

Cited by 139 publications

(155 citation statements)

References 73 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…Alternatively, they could reflect different stages of disease progression [48] or that decreased sterol synthesis and accumulation of cholesterol in neuronal membranes represent two distinct mechanisms likely affecting neuronal survival in HD [52]. In agreement, it was recently shown that altered cholesterol homeostasis in HD results from decreased cholesterol synthesis and dysregulation of its clearance due deficient expression of CYP46A1, the rate limiting enzyme for cholesterol degradation [53]. Our GC/MS results suggest that, in mice consuming a regular diet, cholesterol levels in plasma are reduced in HD.…”

Section: Discussionmentioning

confidence: 99%

“…Only an integral treatment of body and brain alterations will alleviate the wide gamut of HD symptoms [74]. A step forward could be a combination therapy including a special diet and direct administration of cholesterol into the brain, e.g., by using modified cholesterol nanoparticles able to cross the BBB [75], or by stimulating cholesterol metabolism and efflux if, as some studies suggest, it accumulates in brain cell membranes [46, 53]. …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

Chen

Tran

Hwang

et al. 2016

JHD

View full text Add to dashboard Cite

Background Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable dance-like movements, as well as cognitive deficits and mood changes. A feature of HD is a metabolic disturbance that precedes neurological symptoms. In addition, brain cholesterol synthesis is significantly reduced, which could hamper synaptic transmission. Objective Alterations in lipid metabolism as a potential target for therapeutic intervention in the R6/2 mouse model of HD were examined. Methods Electrophysiological recordings in vitro examined the acute effects of cholesterol-modifying drugs. In addition, behavioral testing, effects on synaptic activity, and measurements of circulating and brain tissue concentrations of cholesterol and the ketone β-hydroxybutyrate (BHB), were examined in symptomatic R6/2 mice and littermate controls raised on normal chow or a ketogenic diet (KD). Results Whole-cell voltage clamp recordings of striatal medium-sized spiny neurons (MSNs) from symptomatic R6/2 mice showed increased frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) compared with littermate controls. Incubation of slices in cholesterol reduced the frequency of large-amplitude sIPSCs. Addition of BHB or the Liver X Receptor (LXR) agonist T0901317 reduced the frequency and amplitude of sIPSCs. Surprisingly, incubation in simvastatin to reduce cholesterol levels also decreased the frequency of sIPSCs. HD mice fed the KD lost weight more gradually, performed better in an open field, had fewer stereotypies and lower brain levels of cholesterol than mice fed a regular diet. Conclusions Lipid metabolism represents a potential target for therapeutic intervention in HD. Modifying cholesterol or ketone levels acutely in the brain can partially rescue synaptic alterations, and the KD can prevent weight loss and improve some behavioral abnormalities.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

Chen

Tran

Hwang

et al. 2016

JHD

View full text Add to dashboard Cite

show abstract

“…A combination of genetic and dietary factors cause atherosclerosis that is associated with elevated serum cholesterol and cholesterol accumulation in macrophage foam cells and vascular smooth muscle cells (Buja et al, 1979). CYP46A1 depletion in the striatum of mice mimics Huntington's disease phenotypes and increases the cholesterol level in the brain (Boussicault et al, 2016). Cholesterol accumulation is therefore toxic to adrenocortical as well as other cells under physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

Burns

Kerppola

2017

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSETo further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR-101 (PD132301-02). EXPERIMENTAL APPROACHWe compared the effects of ATR-101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC-derived cell lines. We examined the effects of these compounds in combination with methyl-β-cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds. KEY RESULTSATR-101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC-derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl-β-cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR-101. ATR-101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR-101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR-101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR-101. ATR-101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation. CONCLUSIONS AND IMPLICATIONSInhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR-101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC. IntroductionControl of the levels of cholesterol (The term "cholesterol" is used to denote unesterified cholesterol in this paper) is essential for cell functions and viability (see Maxfield and Van Meer, 2010). The cholesterol levels in adrenocortical cells are affected by many pathways, some of which are unique to the adrenal cortex. Studies of anti-atherosclerosis agents have identified compounds that cause selective degeneration of the adrenal cortex (adrenalytic activity) in several species (Dominick et al., 1993;Reindel et al., 1994;Matsuo et al., 1996;Sliskovic et al., 1998;Tanaka et al., 1998). Here we have investigated the adrenalytic compound ATR-101, also known as PD132301-02, as a prospective agent for the treatment of adrenocortical carcinoma (ACC). We focused on ATR-101 because of its cytotoxicity in ACC-derived cells and its antixenograft and adrenalytic activities (Cheng et al., 2016). ACC is a rare cancer that has few treatment options. The adrenalytic compound mitotane is a first-line drug for ACC treatment despite its poor efficacy, unfavourable pharmacokinetics, severe side effects and potential drug interactions (Maiter et al., 2016). Clinical trials of molecularly targeted agents...

show abstract

“…Both mouse models and human patients with HD exhibit defects in cholesterol homeostasis, with decreased levels of CYP46A1 implicated in both HD patients and the R6/2 Huntington's mouse model [78]. Knockdown of CYP46A1 in the mouse striatum reproduces HD-like striatal neuron degeneration and rotarod deficits while overexpression of CYP46A1 in the striatum of R6/2 mice reduces the severity of cell loss and HTT aggregates and improve motor function [79]. It is unclear if this mechanism involves CYP46A1-dependent production of 24-OHC and the subsequent activation of LXRs, however, substantial overproduction of 24-OHC in a CYP46 overexpressing mouse was unable to effect LXR activation in the brain or liver [80].…”

Section: Lxrs In Cns Disordersmentioning

confidence: 99%

LXR Regulation of Brain Cholesterol: From Development to Disease

Courtney

Landreth

2016

Trends in Endocrinology & Metabolism

125

105

View full text Add to dashboard Cite

Liver X Receptors (LXRs) are master regulators of cholesterol homeostasis and inflammation in the central nervous system (CNS). The brain, which contains a disproportionately large amount of the body's total cholesterol (~25%), requires a complex and delicately balanced cholesterol metabolism to maintain neuronal function. Dysregulation of cholesterol metabolism has been implicated in a number of neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases, among others. Due to their cholesterol sensing and anti-inflammatory activities, LXRs are positioned centrally in the everyday maintenance of central nervous system function. This review will focus on recent research into the role of LXRs in the CNS during normal development and homeostasis and in disease states.

show abstract

CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease

Cited by 139 publications

References 73 publications

Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

LXR Regulation of Brain Cholesterol: From Development to Disease

Contact Info

Product

Resources

About