NICHD, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Mol Cell Proteomics. 2010 Jul;9(7):1461-75. doi: 10.1074/mcp.M900548-MCP200. Epub 2010 Mar 19.
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.
史密斯-莱姆利-奥皮茨综合征（SLOS）和植物固醇血症是由 7-脱氢胆固醇还原酶（DHCR7）和植物固醇 5-去饱和酶（SC5D）突变引起的具有认知缺陷的畸形综合征，分别。DHCR7 编码坎德彻-拉塞尔胆固醇生物合成途径中的最后一种酶，DHCR7 活性受损导致胆固醇缺乏和 7-脱氢胆固醇积累。SC5D 催化从植物固醇合成 7-脱氢胆固醇。SC5D 活性受损导致类似的胆固醇缺乏，但植物固醇积累。尽管两种综合征的遗传和生化原因已知，但导致发育缺陷的病理生理过程仍不清楚。为了研究 SLOS 和植物固醇血症神经症状的病理生理机制，我们对 SLOS 和植物固醇血症小鼠脑组织进行了定量蛋白质组学分析，并鉴定了 Dhcr7(Delta3-5/Delta3-5)和 Sc5d(-/-)E18.5 胚胎中受影响的多个生物学途径。这些途径包括甲羟戊酸代谢、细胞凋亡、糖酵解、氧化应激、蛋白质生物合成、细胞内运输和细胞骨架的改变。比较 Dhcr7(Delta3-5/Delta3-5)和 Sc5d(-/-)脑组织中蛋白质组的变化有助于阐明受干扰的蛋白质表达是由于胆固醇减少还是固醇前体的毒性作用。蛋白质组学结果的验证证实了异戊烯基和胆固醇合成酶的表达增加。这种异戊烯基合成的改变可能是导致 Rab7 翻译后修饰改变的基础，Rab7 是一种小 GTP 酶，其功能依赖于 geranylgeranyl 的 prenylation，我们在本研究中鉴定并验证了这一点。这些数据表明，尽管 Dhcr7(Delta3-5/Delta3-5)和 Sc5d(-/-)胚胎脑组织中胆固醇合成受损，但非甾体异戊烯的合成可能增加，从而导致 SLOS 和植物固醇血症的发生。这项蛋白质组学研究为 SLOS 和植物固醇血症的病理生理机制提供了深入了解，了解这些病理生理变化将有助于指导 SLOS 和植物固醇血症的临床治疗。
