Survival of adult neurons lacking cholesterol synthesis in vivo

Fünfschilling, Ursula; Saher, Gesine; Xiao, Le; Möbius, Wiebke; Nave, Klaus‐Armin

doi:10.1186/1471-2202-8-1

Cited by 113 publications

(92 citation statements)

References 29 publications

(34 reference statements)

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“…48 Furthermore, it was shown that some adult neurons no longer require endogenous cholesterol synthesis and can fully meet their cholesterol needs by uptake from their surroundings. 49 Therefore, the neuroprotective effects demonstrated by the present work are probably cholesterol independent.…”

Section: Possible Statin Mechanisms Involved In Functional Neuroprotementioning

confidence: 92%

Simvastatin Improves Retinal Ganglion Cell Survival and Spatial Vision after Acute Retinal Ischemia/Reperfusion in Mice

Krempler

Schmeer

Isenmann

et al. 2011

Invest. Ophthalmol. Vis. Sci.

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This specific combination of behavioral measurements of visual function, cortical activity imaging, and histologic analyses is ideally suited to follow ischemia-induced changes and to monitor the effect of therapeutic approaches. Statin therapy may be a promising pharmacologic tool for the treatment of acute retinal ischemia in particular because, in our study, simvastatin was applied after ischemia, a treatment regimen with much greater clinical relevance than preventive administration, as in previous studies.

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Section: Possible Statin Mechanisms Involved In Functional Neuroprotementioning

confidence: 92%

Simvastatin Improves Retinal Ganglion Cell Survival and Spatial Vision after Acute Retinal Ischemia/Reperfusion in Mice

Krempler

Schmeer

Isenmann

et al. 2011

Invest. Ophthalmol. Vis. Sci.

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“…Subsequent investigations generated conditional mouse lines, with cell-type deletion of squalene synthase and thus cholesterol production in specific cells in the brain. When squalene synthase was eliminated only in myelinating glia cells (41,42), mutant animals were born but showed severe hypomyelination, and one third of the newborn died. When squalene synthase was deleted embryonically in neuronal and glial precursors, no pups were born (41,42), highlighting the importance of brain cholesterol synthesis during development for fetal survival.…”

Section: Fig 6 Expression Of Hsd17b7 In the Embryo By In Situ Hybrimentioning

confidence: 98%

“…When squalene synthase was eliminated only in myelinating glia cells (41,42), mutant animals were born but showed severe hypomyelination, and one third of the newborn died. When squalene synthase was deleted embryonically in neuronal and glial precursors, no pups were born (41,42), highlighting the importance of brain cholesterol synthesis during development for fetal survival. Our deletion of Hsd17b7, the last enzyme in the cholesterol biosynthetic pathway to be discovered, further establishes the importance of cholesterol synthesis in brain development.…”

Section: Fig 6 Expression Of Hsd17b7 In the Embryo By In Situ Hybrimentioning

confidence: 98%

Prolactin Receptor-Associated Protein/17β-Hydroxysteroid Dehydrogenase Type 7 Gene (Hsd17b7) Plays a Crucial Role in Embryonic Development and Fetal Survival

Shehu¹,

Mao²,

Gibori³

et al. 2008

Molecular Endocrinology

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Our laboratory has previously cloned and purified a protein named PRAP (prolactin receptor-associated protein) that was shown to be a novel 17beta-hydroxysteroid dehydrogenase (HSD) enzyme with dual activity. This enzyme, renamed HSD17B7 or PRAP/17beta-HSD7, converts estrone to estradiol and is also involved in cholesterol biosynthesis. The major site of its expression is the corpus luteum of a great number of species including rodents and humans. To examine the functional significance of HSD17B7 in pregnancy, we generated a knockout mouse model with targeted deletions of exons 1-4 of this gene. We anticipated a mouse with a severe fertility defect due to its inability to regulate estrogen levels during pregnancy. The heterozygous mutant mice are normal in their development and gross anatomy. The females cycle normally, and both male and female are fertile with normal litter size. To our surprise, the breeding of heterozygous mice yielded no viable HSD17B7 null mice. However, we found HSD17B7 null embryo alive in utero on d 8.5 and d 9.5. By d 10.5, the fetuses grow and suffer from severe brain malformation and heart defect. Because the brain depends on in situ cholesterol biosynthesis for its development beginning at d 10, the major cause of fetal death appears to be due to the cholesterol synthetic activity of this enzyme. By ablating HSD17B7 function, we have uncovered, in vivo, an important requirement for this enzyme during fetal development.

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“…Glutamate re-uptake is believed to promote the release of ascorbate via heteroexchange at the site of glutamate transport. Ascorbate release, in turn, may modulate the postsynaptic action of glutamate by blocking NMDA receptors (Kiyatkin and Rebec 1998;Rebec and Sandstrom 2007).…”

Section: Introductionmentioning

confidence: 99%

Effect of Chronic Administration of Morphine on the Gene Expression Level of Sodium-Dependent Vitamin C Transporters in Rat Hippocampus and Lumbar Spinal Cord

et al. 2009

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Chronic morphine leads to dependence, tolerance, and neural apoptosis. Vitamin C inhibits the withdrawal syndrome in morphine-dependent subjects and prevents apoptosis in experimental models. Sodium-dependent vitamin C transporter (SVCT) type-2 is the main transporter for carrying vitamin C into the brain and neural cells. The mechanism(s) by which vitamin C inhibits morphine dependence in not understood. SVCT activity determines the vitamin C availably within the nervous system. We have examined the alterations in the expression of SVCT1, SVCT2, and its splice variants in morphine-tolerant rats. Morphine (20 mg/kg) was injected twice/day to male rats for either 7 or 14 days. The development of analgesic tolerance was assessed using tail-flick test. Lumbar spinal cord and the hippocampus were isolated for RNA extraction. Semiquantitative reverse transcriptase-polymerase chain reaction method was used to assess the levels of gene expression. Administration of morphine for 7 or 14 days reduced the expression level of SVCT2 in both hippocampus and dorsal lumbar spinal cord of rats. SVCT2 expression was reduced in vitamin C-, and vitamin C combined with morphine-treated animals. Results did not show SVCT2 splice variation. SVCT1 did not express in control or morphine-treated rats. It seems that reduced expression level of SVCT2 might be involved in the development of morphine side effects such as tolerance and dependency.

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Survival of adult neurons lacking cholesterol synthesis in vivo

Cited by 113 publications

References 29 publications

Simvastatin Improves Retinal Ganglion Cell Survival and Spatial Vision after Acute Retinal Ischemia/Reperfusion in Mice

Simvastatin Improves Retinal Ganglion Cell Survival and Spatial Vision after Acute Retinal Ischemia/Reperfusion in Mice

Prolactin Receptor-Associated Protein/17β-Hydroxysteroid Dehydrogenase Type 7 Gene (Hsd17b7) Plays a Crucial Role in Embryonic Development and Fetal Survival

Effect of Chronic Administration of Morphine on the Gene Expression Level of Sodium-Dependent Vitamin C Transporters in Rat Hippocampus and Lumbar Spinal Cord

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