Oxysterols as biomarkers in neurodegenerative diseases

Leoni, Valerio; Caccia, Claudio

doi:10.1016/j.chemphyslip.2011.04.002

Cited by 190 publications

(124 citation statements)

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“…Cholesterol synthesis and transport in oligodendrocytes is essential for optimal myelination and remyelination, and defective homeostasis has been implicated in several neurological diseases, including MS (Chalmin et al, 2015;Leoni and Caccia, 2011).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Wang¹,

Sadovnick²,

Traboulsee³

et al. 2016

Neuron

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SUMMARYMultiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3 identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.

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Section: Discussionmentioning

confidence: 99%

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Wang¹,

Sadovnick²,

Traboulsee³

et al. 2016

Neuron

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“…Astrocyte expressing HSD3B7 is responsible for degradation of oxysterol, the active oxidized product of cholesterol, which can be used as a marker of brain atrophy in patients holding aging neurons with AD and HD (Leoni & Caccia, 2011; Rutkowska, Preuss, Gessier, Sailer, & Dev, 2015). Additionally, the production of the dafachronic acids, a nuclear receptor for bile acids, can be regulated by a conserved 3 beta‐ HSD to participate in cholesterol, bile acid metabolism, and longevity (Wollam et al., 2012).…”

Section: Discussionmentioning

confidence: 99%

The association between HSD3B7 gene variant and Parkinson's disease in ethnic Chinese

Wang

Sun

et al. 2018

Brain and Behavior

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ObjectivesStudies at the genomewide level of Parkinson's disease (PD) suggested a significant association between the Hydroxy‐delta‐5‐steroid dehydrogenase, 3 beta‐ and steroid delta isomerase 7 (HSD3B7) gene rs9938550 variant and a decreased risk for PD. But its effect has only been discussed in Caucasian populations, and no phenotypic characteristics were included. To investigate the novel variant for PD in Chinese Han populations, we performed an association analysis of rs9938550 variant in a large cohort.MethodsUsing a case–control methodology, a total of 2,239 subjects (1,072 sporadic patients with PD and 1,167 control) were genotyped and the genetic association was analyzed.ResultsNo significant association was found between allele A of rs9938550 and PD in the entire cohort (p = .079). However, the frequency of allele A was lower in late‐onset PD (LOPD) as compared with controls older than 50 years (OR = 0.62, 95% CI: 0.45–0.85, p adjust = .002). Relatively lower Unified Parkinson's Disease Rating Scale scores were demonstrated in mid‐ to late‐stage PD with GA + AA genotypes than GG genotype (p adjust = .018), while other clinical features were similar between carriers and noncarriers.ConclusionsOur results support that the HSD3B7 rs9938550 variant, which is likely linked to bile acid biosynthesis, reduces the risk of LOPD in Chinese patients and might induce a benign clinical performance.

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“…In early stages of Alzheimer's disease, there are significantly higher CSF concentrations of 24S-hydroxycholesterol suggesting increased cholesterol turnover in the CNS during degeneration (Leoni & Caccia, 2011). These levels decrease as the disease advances, possibly reflecting the loss of cells expressing cholesterol 24S-hydroxylase, the enzyme responsible for the conversion of brain cholesterol into 24S-hydroxycholesterol.…”

Section: Alzheimer's Diseasementioning

confidence: 98%

“…The CSF levels of 24S-hydroxycholesterol appears to be sensitive to changes in the brain (possibly because they are not affected by hepatic clearance rates of this oxysterol) and may represent better markers both for neurodegenerative diseases and for disturbances in the blood brain barrier (Leoni & Caccia, 2011). In early stages of Alzheimer's disease, there are significantly higher CSF concentrations of 24S-hydroxycholesterol suggesting increased cholesterol turnover in the CNS during degeneration (Leoni & Caccia, 2011).…”

Section: Alzheimer's Diseasementioning

confidence: 99%