Narayan Sujatha, Head Steven R, Gilmartin Timothy J, Dean Brian, Thomas Elizabeth A
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
J Neurosci Res. 2009 Jan;87(1):278-88. doi: 10.1002/jnr.21822.
As the field of glycobiology grows, important roles for glycolipids and glycoproteins in neurological disorders are being increasingly appreciated. However, few studies have explored the involvement of these molecules in the pathology of psychiatric illnesses. We investigated molecular differences related to glycobiology in subjects with schizophrenia by analyzing gene expression profiles using a focused glycogene chip, a custom-designed oligonucleotide array containing genes encoding proteins related to glycobiology, including glycosyltransferases, carbohydrate-binding proteins, proteoglycans, and adhesion molecules. We measured expression profiles in prefrontal cortical (BA46) samples from schizophrenic subjects and matched controls. We find differential expression of genes particularly related to glycosphingolipid/sphingolipid metabolism and N- and O-linked glycan biosynthesis in subjects with schizophrenia. Expression decreases of seven genes associated with these pathways, UGT8, SGPP1, GALC, B4GALT6, SPTLC2, ASAH1, and GAL3ST1, were validated by quantitative PCR in schizophrenic subjects with short-term illness. Only one of these genes, SPTLC2, showed differential expression in chronic schizophrenic subjects, although an increase in expression was observed. Covariate analysis showed that the expression of five of these genes was significantly positively correlated with age in schizophrenic, but not control, subjects. These changing patterns of expression could represent an adaptive response to pathology with disease progression or a compensatory effect of antipsychotic medication, although no significant correlations between gene expression levels and drug doses were observed. Disruption of sphingolipid metabolism early in illness could result in widespread downstream effects encompassing diverse pathological deficits already described in schizophrenia, especially those involving myelination and oligodendrocyte function; hence, this system may represent an important link in schizophrenia pathology.
随着糖生物学领域的发展，糖脂和糖蛋白在神经疾病中的重要作用越来越受到重视。然而，很少有研究探讨这些分子在精神疾病病理学中的作用。我们通过使用聚焦糖基因芯片分析基因表达谱，对精神分裂症患者中与糖生物学相关的分子差异进行了研究。该芯片是一种定制设计的寡核苷酸阵列，包含编码与糖生物学相关蛋白质的基因，如糖基转移酶、碳水化合物结合蛋白、蛋白聚糖和黏附分子。我们测量了精神分裂症患者和匹配对照的前额叶皮质（BA46）样本中的表达谱。我们发现精神分裂症患者中与糖鞘脂/鞘脂代谢以及N-和O-连接聚糖生物合成特别相关的基因存在差异表达。与这些途径相关的七个基因UGT8、SGPP1、GALC、B4GALT6、SPTLC2、ASAH1和GAL3ST1的表达下降，在短期患病的精神分裂症患者中通过定量PCR得到了验证。这些基因中只有SPTLC2在慢性精神分裂症患者中显示出差异表达，不过观察到的是表达增加。协变量分析表明，这些基因中的五个基因的表达在精神分裂症患者而非对照患者中与年龄显著正相关。这些表达变化模式可能代表了随着疾病进展对病理学的适应性反应或抗精神病药物的补偿作用，尽管未观察到基因表达水平与药物剂量之间存在显著相关性。疾病早期鞘脂代谢的破坏可能导致广泛的下游效应，包括精神分裂症中已描述的各种病理缺陷，特别是那些涉及髓鞘形成和少突胶质细胞功能的缺陷；因此，这个系统可能是精神分裂症病理学中的一个重要环节。
