Abstract
Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis are malformation syndromes with cognitive deficits caused by mutations of 7-dehydrocholesterol reductase (DHCR7) and lathosterol 5-desaturase (SC5D), respectively. DHCR7 encodes the last enzyme in the Kandutsch-Russel cholesterol biosynthetic pathway, and impaired DHCR7 activity leads to a deficiency of cholesterol and an accumulation of 7-dehydrocholesterol. SC5D catalyzes the synthesis of 7-dehydrocholesterol from lathosterol. Impaired SC5D activity leads to a similar deficiency of cholesterol but an accumulation of lathosterol. Although the genetic and biochemical causes underlying both syndromes are known, the pathophysiological processes leading to the developmental defects remain unclear. To study the pathophysiological mechanisms underlying SLOS and lathosterolosis neurological symptoms, we performed quantitative proteomics analysis of SLOS and lathosterolosis mouse brain tissue and identified multiple biological pathways affected in Dhcr7(Delta3-5/Delta3-5) and Sc5d(-/-) E18.5 embryos. These include alterations in mevalonate metabolism, apoptosis, glycolysis, oxidative stress, protein biosynthesis, intracellular trafficking, and cytoskeleton. Comparison of proteome alterations in both Dhcr7(Delta3-5/Delta3-5) and Sc5d(-/-) brain tissues helps elucidate whether perturbed protein expression was due to decreased cholesterol or a toxic effect of sterol precursors. Validation of the proteomics results confirmed increased expression of isoprenoid and cholesterol synthetic enzymes. This alteration of isoprenoid synthesis may underlie the altered posttranslational modification of Rab7, a small GTPase that is functionally dependent on prenylation with geranylgeranyl, that we identified and validated in this study. These data suggested that although cholesterol synthesis is impaired in both Dhcr7(Delta3-5/Delta3-5) and Sc5d(-/-) embryonic brain tissues the synthesis of nonsterol isoprenoids may be increased and thus contribute to SLOS and lathosterolosis pathology. This proteomics study has provided insight into the pathophysiological mechanisms of SLOS and lathosterolosis, and understanding these pathophysiological changes will help guide clinical therapy for SLOS and lathosterolosis.
Highlights
Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis are malformation syndromes with cognitive deficits caused by mutations of 7-dehydrocholesterol reductase (DHCR7) and lathosterol 5-desaturase (SC5D), respectively
We report the use of two-dimensional electrophoresis (2-DE) mass spectrometry proteomics analysis to identify proteins with altered expression in brain tissue from both Dhcr7 and Sc5d mutants with the goal of identifying novel pathophysiological mechanisms contributing to the neurological deficits in these two inborn errors of cholesterol synthesis
It is unlikely that a single pathogenic mechanism can explain the pleiotropic phenotypic findings and symptoms observed in SLOS and lathosterolosis [1, 46]
Summary
To study the pathophysiological mechanisms underlying SLOS and lathosterolosis neurological symptoms, we performed quantitative proteomics analysis of SLOS and lathosterolosis mouse brain tissue and identified multiple biological pathways affected in Dhcr7⌬3–5/⌬3–5 and Sc5d؊/؊ E18.5 embryos These include alterations in mevalonate metabolism, apoptosis, glycolysis, oxidative stress, protein biosynthesis, intracellular trafficking, and cytoskeleton. The abbreviations used are: SLOS, Smith-Lemli-Opitz syndrome; 2-DE, two-dimensional electrophoresis; 7DHC, 7-dehydrocholesterol; DHCR7, 7-dehydrocholesterol reductase; GGPS, geranylgeranyldiphosphate synthase; HMGCS1, cytoplasmic hydroxymethylglutaryl-CoA synthase; IDI1, isopentenyl-diphosphate ⌬-isomerase 1; ROS, reactive oxygen species; SC5D, lathosterol 5-desaturase; SREBP, sterol regulatory element-binding protein; c-SREBP, cleaved sterol regulatory element-binding protein; DSF, detergent-soluble fraction; DRM, detergent-resistant membrane. We report the use of two-dimensional electrophoresis (2-DE) mass spectrometry proteomics analysis to identify proteins with altered expression in brain tissue from both Dhcr and Sc5d mutants with the goal of identifying novel pathophysiological mechanisms contributing to the neurological deficits in these two inborn errors of cholesterol synthesis. Our data are consistent with the hypothesis that both cholesterol deficiency and increased precursor sterol levels contribute to SLOS and lathosterolosis pathology
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