Cholesterol Synthesis and Nerve Regeneration

Abstract

In this report, we examine the requirement of cholesterol biosynthesis and its axonal transport for goldfish optic nerve regeneration. Cholesterol, labeled by intraocular injection of [3H]mevalonolactone, exhibited a delayed appearance in the optic tectum. Squalene and other minor components were labeled but not transported. Following optic nerve crush, the amount of labeled cholesterol transport was elevated, while retinal labeling was not altered relative to control fish. A requirement for cholesterol biosynthesis is inferred from the inhibition of neurite outgrowth in retinal explants caused by the cholesterol synthesis inhibitor, 20,25-diazacholesterol. The inhibition of growth could be overcome by addition of mevalonolactone, but not cholesterol, to the medium. Intraperitoneal administration of 200 nmol of diazacholesterol resulted in 92-98% inhibition of retinal cholesterol synthesis and accumulation of labeled desmosterol and other lipids in fish retina and brain which persisted for 2 weeks. Diazacholesterol-treated fish showed no reduction in the amount of lipid-soluble radioactivity transported following intraocular injection of [3H]mevalonolactone, but there were alterations in the chromatographic pattern of the transported labeled lipids. In contrast to its effects on neurite outgrowth in vitro, diazacholesterol did not inhibit optic nerve regeneration in vivo, as measured both by arrival of labeled rapidly transported protein at the tectum and by time required for the return of visual function.

ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function

“…In addition to the ER stress-related genes, we found significant enrichment of cholesterol biosynthesis-related genes among downstream targets of Derlin-1 ( Figures 5 A and 5B). Efficient cholesterol biosynthesis is essential for neurite elongation because neuronal membranes contain high levels of cholesterol ( Heacock et al., 1984 ). To examine whether Derlin-1 and Derlin-2 regulate the transcription of cholesterol biosynthesis-related genes, total RNAs harvested from the cerebella of Derl1 NesCre , Derl2 NesCre , and control mice were analyzed using qPCR.…”

Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats

“…Therefore, cells in the brain rely entirely on cholesterol synthesis, a resource‐intense process that requires energy, molecular oxygen and 21 enzymes (Bloch 1964; Waterham 2006; Ikonen 2008). Previous studies indicate that neurons have a particularly high demand for cholesterol to form and maintain axons (Heacock et al. 1984; Hayashi et al.…”

“…Therefore, cells in the brain rely entirely on cholesterol synthesis, a resource-intense process that requires energy, molecular oxygen and 21 enzymes (Bloch 1964;Waterham 2006;Ikonen 2008). Previous studies indicate that neurons have a particularly high demand for cholesterol to form and maintain axons (Heacock et al 1984;Hayashi et al 2004), dendrites (Fan et al 2002;Goritz et al 2005) and synaptic connections (Mauch et al 2001;Pfrieger 2003b). It has been estimated that neurons renew 20% of their cholesterol content daily (Dietschy and Turley 2004).…”

Precursors for Cholesterol Synthesis (7‐Dehydrocholesterol, 7‐Dehydrodesmosterol, and Desmosterol): Cholesterol/7‐Dehydrocholesterol Ratio as an Index of Development and Aging in PNS but Not in CNS

“…Nineteen discrete reactions are used to convert lanosterol to cholesterol, and the side-chain saturation can be either the first or the last reaction in the sequence (Schroepfer, 1982;Rilling and Chayet, 1985). Use of various hypocholesterolemic drugs has shown accumulation of precursors (Ramsey et al, 197 1 ;Suzuki et al, 1974;Ramsey, 1977;Heacock et al, 1984).…”