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Age-dependent increase in desmosterol restores DRM formation and membrane-related functions in cholesterol-free DHCR24-/- mice.

ABSTRACT: Cholesterol is a prominent modulator of the integrity and functional activity of physiological membranes and the most abundant sterol in the mammalian brain. DHCR24-knock-out mice lack cholesterol and accumulate desmosterol with age. Here we demonstrate that brain cholesterol deficiency in 3-week-old DHCR24(-/-) mice was associated with altered membrane composition including disrupted detergent-resistant membrane domain (DRM) structure. Furthermore, membrane-related functions differed extensively in the brains of these mice, resulting in lower plasmin activity, decreased beta-secretase activity and diminished Abeta generation. Age-dependent accumulation and integration of desmosterol in brain membranes of 16-week-old DHCR24(-/-) mice led to the formation of desmosterol-containing DRMs and rescued the observed membrane-related functional deficits. Our data provide evidence that an alternate sterol, desmosterol, can facilitate processes that are normally cholesterol-dependent including formation of DRMs from mouse brain extracts, membrane receptor ligand binding and activation, and regulation of membrane protein proteolytic activity. These data indicate that desmosterol can replace cholesterol in membrane-related functions in the DHCR24(-/-) mouse.

SUBMITTER: Kuehnle K

PROVIDER: S-EPMC2758381 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Age-dependent increase in desmosterol restores DRM formation and membrane-related functions in cholesterol-free DHCR24-/- mice.

Kuehnle Katrin K Ledesma Maria D MD Kalvodova Lucie L Smith Alicia E AE Crameri Arames A Skaanes-Brunner Fabienne F Thelen Karin M KM Kulic Luka L Lütjohann Dieter D Heppner Frank L FL Nitsch Roger M RM Mohajeri M Hasan MH

Neurochemical research 20081225 6

Cholesterol is a prominent modulator of the integrity and functional activity of physiological membranes and the most abundant sterol in the mammalian brain. DHCR24-knock-out mice lack cholesterol and accumulate desmosterol with age. Here we demonstrate that brain cholesterol deficiency in 3-week-old DHCR24(-/-) mice was associated with altered membrane composition including disrupted detergent-resistant membrane domain (DRM) structure. Furthermore, membrane-related functions differed extensivel ...[more]

PMID: 19115107

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Project description:Cholesterol synthesis in the fetal brain is inhibited because activity of DHCR24 (24-dehydrocholesterol reductase) is insufficient, causing concentrations of the precursor desmosterol to increase temporarily to 15-25% of total sterols at birth. We demonstrate that failure of DHCR24 to be adequately upregulated during periods of elevated cholesterol synthesis in the brain results from the presence in its promoter of the repressor element 1 (RE1) nucleotide sequence that binds the RE1-silencing transcription factor (REST) and that REST, generally reduced in neural tissues, uncharacteristically but not without precedent, enhances DHCR24 transcription. DHCR24 and REST mRNA levels are reduced 3- to 4-fold in fetal mouse brain compared to liver (p < 0.001). Chromatin immunoprecipitation assays suggested that REST binds to the human DHCR24 promoter in the vicinity of the predicted human RE1 sequence. Luminescent emission from a human DHCR24 promoter construct with a mutated RE1 sequence was reduced 2-fold compared to output from a reporter with wild-type RE1 (p < 0.005). Silencing REST in HeLa cells resulted in significant reductions of DHCR24 mRNA (2-fold) and DHCR24 protein (4-fold). As expected, relative concentrations of ?(24)-cholesterol precursor sterols increased 3- to 4-fold, reflecting the inhibition of DHCR24 enzyme activity. In contrast, mRNA levels of DHCR7 (sterol 7-dehydrocholesterol reductase), a gene essential for cholesterol synthesis lacking an RE1 sequence, and concentrations of HMGR (3-hydroxy-3-methyl-glutaryl-CoA reductase) enzyme protein were both unaffected. Surprisingly, a dominant negative fragment of REST consisting of just the DNA binding domain (about 20% of the protein) and full-length REST enhanced DHCR24 expression equally well. Furthermore, RE1 and the sterol response element (SRE), the respective binding sites for REST and the SRE binding protein (SREBP), are contiguous. These observations led us to hypothesize that REST acts because it is bound in close proximity to SREBP, thus amplifying its ability to upregulate DHCR24. It is likely that modulation of DHCR24 expression by REST persisted in the mammalian genome either because it does no harm or because suppressing metabolically active DHCR24 while providing abundant quantities of the multifunctional sterol desmosterol during neural development proved useful.

Project description:Shear viscosity of lipid membranes dictates how fast lipids, proteins, and other membrane constituents travel along the membrane and rotate around their principal axis, thus governing the rates of diffusion-limited reactions taking place at membranes. In this framework, the heterogeneity of biomembranes indicates that cells could regulate these rates via varying local viscosities. Unfortunately, experiments to probe membrane viscosity under various conditions are tedious and error prone. Molecular dynamics simulations provide an attractive alternative, especially given that recent theoretical developments enable the elimination of finite-size effects in simulations. Here, we use a variety of different equilibrium methods to extract the shear viscosities of lipid membranes from both coarse-grained and all-atom molecular dynamics simulations. We systematically probe the variables relevant for cellular membranes, namely, membrane protein crowding, cholesterol concentration, and the length and saturation level of lipid acyl chains, as well as temperature. Our results highlight that in their physiologically relevant ranges, protein concentration, cholesterol concentration, and temperature have significantly larger effects on membrane viscosity than lipid acyl chain length and unsaturation level. In particular, the crowding with proteins has a significant effect on the shear viscosity of lipid membranes and thus on the diffusion occurring in the membranes. Our work also provides the largest collection of membrane viscosity values from simulation to date, which can be used by the community to predict the diffusion coefficients or their trends via the Saffman-Delbrück description. Additionally, it is worth emphasizing that diffusion coefficients extracted from simulations exploiting periodic boundary conditions must be corrected for the finite-size effects prior to comparison with experiment, for which the present collection of viscosity values can readily be used. Finally, our thorough comparison to experiments suggests that there is room for improvement in the description of bilayer dynamics provided by the present force fields.

Dataset Information

Age-dependent increase in desmosterol restores DRM formation and membrane-related functions in cholesterol-free DHCR24-/- mice.

Publications

Age-dependent increase in desmosterol restores DRM formation and membrane-related functions in cholesterol-free DHCR24-/- mice.

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