Temporal changes in the brain lipidome during neurodevelopment of Smith–Lemli–Opitz syndrome mice

Li, Amy; Hines, Kelly M.; Ross, Dylan H.; MacDonald, James W.; Xu, Libin

doi:10.1039/d2an00137c

Cited by 2 publications

(3 citation statements)

References 65 publications

(92 reference statements)

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“…Our previous HILIC-IM-MS study highlighted certain changes in lipids across developmental timepoints (23), and we were interested to see if similar changes would be detected via MALDI-IM-MSI, but with a spatial resolution component. ESI and MALDI are two fundamentally different ionization sources, which could lead to different observations of lipids and differences due to ion suppression of low abundant lipids when analyzing the whole brain homogenates.…”

Section: Resultsmentioning

confidence: 99%

“…The Dhcr7 tm1Gst ( Dhcr7 Ex 8 ) mouse model of SLOS is equivalent to the IVS8-1G>C in humans and is associated with a severe phenotype, causing postnatal lethality within 24 hours of birth in homozygous mice. Previously, we have conducted an untargeted lipidomics study of the brain over the time course of development in this mouse model of SLOS using hydrophilic interaction liquid chromatography-ion mobility-mass spectrometry (HILIC-IM-MS) (23). While the study was informative on global changes in various lipid classes and species as embryonic development progressed, whole brain tissue homogenization eliminated the rich spatial information present within the brain.…”

Section: Introductionmentioning

confidence: 99%

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MALDI-IM-MS Imaging of Brain Sterols and Lipids in a Mouse Model of Smith-Lemli-Opitz Syndrome

Li,

2023

Preprint

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Smith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by genetic mutations in theDHCR7gene, encoding the enzyme 3β-hydroxysterol-Δ7-reductase (DHCR7) that catalyzes the last step of cholesterol synthesis. The resulting deficiency in cholesterol and accumulation of its precursor, 7-dehydrocholesterol (7-DHC), have a profound impact on brain development, which manifests as developmental delay, cognitive impairment, and behavioral deficits. To understand how the brain regions are differentially affected by the defective Dhcr7, we aim to map the regional distribution of sterols and other lipids in neonatal brains from aDhcr7-KO mouse model of SLOS, using mass spectrometry imaging (MSI). MSI enables spatial localization of biomoleculesin situon the surface of a tissue section, which is particularly useful for mapping the changes that occur within a metabolic disorder such as SLOS, and in an anatomically complex organ such as the brain. In this work, using MALDI-ion mobility (IM)-MSI, we successfully determined the regional distribution of features that correspond to cholesterol, 7-DHC/desmosterol, and the precursor of desmosterol, 7-dehydrodesmosterol, in WT andDhcr7-KO mice. Interestingly, we also observedm/zvalues that match the major oxysterol metabolites of 7-DHC (DHCEO and hydroxy-7-DHC), which displayed similar patterns as 7-DHC. We then identified brain lipids usingm/zand CCS at the Lipid Species-level and curated a database of MALDI-IM-MS-derived lipid CCS values. Subsequent statistical analysis of regions-of-interest allowed us to identify differentially expressed lipids betweenDhcr7-KO and WT brains, which could contribute to defects in myelination, neurogenesis, neuroinflammation, and learning and memory in SLOS.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MALDI-IM-MS Imaging of Brain Sterols and Lipids in a Mouse Model of Smith-Lemli-Opitz Syndrome

Li,

2023

Preprint

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“…Since SLOS is characterized by reduced levels of plasma cholesterol along with accumulation of 7-DHC and its positional isomer 8-DHC ( Porter, 2008 ), clinical characterization of SLOS is predominantly carried out by measurement of altered 7-DHC (and 8-DHC)/cholesterol ratio in the blood serum ( Tint et al, 1995b ). However, there could be additional factors involved in the pathology of SLOS such as oxysterols and hydroxyl derivatives of 7- and 8-DHC, which are suggested to complement defects associated with SLOS ( Wassif et al, 2003 ; Korade et al, 2010 ; Xu et al, 2011 ; Xu et al, 2012 ; Griffiths et al, 2017 ; Li et al, 2022 ; Tomita et al, 2022 ). A recent report has shown that one of the oxidative derivatives of 7-DHC, i.e., 3β, 5α-dihydroxycholest-7-en-6-one (DHCEO) is involved in neurogenic defects in SLOS by causing aberrant premature neurogenesis in both mouse and neural progenitor cells, which could be rescued with antioxidants ( Tomita et al, 2022 ).…”

Section: Smith-lemli-opitz Syndrome: Molecular Etiology and Treatmentmentioning

confidence: 99%

Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis

Chattopadhyay

Sharma²

2023

Front. Mol. Biosci.

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The biosynthesis of cholesterol, an essential component of higher eukaryotic membranes, was worked out by Konrad Bloch (and Feodor Lynen) in the 1960s and they received the Nobel Prize around that time in recognition of their pioneering contributions. An elegant consequence of this was a hypothesis proposed by Konrad Bloch (the Bloch hypothesis) which suggests that each subsequent intermediate in the cholesterol biosynthesis pathway is superior in supporting membrane function in higher eukaryotes relative to its precursor. In this review, we discuss an autosomal recessive metabolic disorder, known as Smith-Lemli-Opitz syndrome (SLOS), associated with a defect in the Kandutsch-Russell pathway of cholesterol biosynthesis that results in accumulation of the immediate precursor of cholesterol in its biosynthetic pathway (7-dehydrocholesterol) and an altered cholesterol to total sterol ratio. Patients suffering from SLOS have several developmental, behavioral and cognitive abnormalities for which no drug is available yet. We characterize SLOS as a manifestation of the Bloch hypothesis and review its molecular etiology and current treatment. We further discuss defective Hedgehog signaling in SLOS and focus on the role of the serotonin1A receptor, a representative neurotransmitter receptor belonging to the GPCR family, in SLOS. Notably, ligand binding activity and cellular signaling of serotonin1A receptors are impaired in SLOS-like condition. Importantly, cellular localization and intracellular trafficking of the serotonin1A receptor (which constitute an important determinant of a GPCR cellular function) are compromised in SLOS. We highlight some of the recent developments and emerging concepts in SLOS pathobiology and suggest that novel therapies based on trafficking defects of target receptors could provide new insight into treatment of SLOS.

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Temporal changes in the brain lipidome during neurodevelopment of Smith–Lemli–Opitz syndrome mice

Abstract: Lipidomics revealed relative temporal changes in lipid abundances in mouse brains during embryonic development and differentially expressed brain lipids between wild-type and Smith–Lemli–Opitz syndrome mice.

Cited by 2 publications

References 65 publications

MALDI-IM-MS Imaging of Brain Sterols and Lipids in a Mouse Model of Smith-Lemli-Opitz Syndrome

MALDI-IM-MS Imaging of Brain Sterols and Lipids in a Mouse Model of Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis

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