The pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein-protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated posttranslational lipid modifications may play a role in multiple neuropsychiatric disorders, including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of S-palmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that, in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (n = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine whether upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1 and prenylation-dependent processing enzymes RCE and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B, and RABGGTB in the cortex from rats treated long-term with haloperidol decanoate and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein-protein interactions and protein localization in schizophrenia.

中文翻译：

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异戊烯基转移酶亚基在死后精神分裂症背外侧前额叶皮质中的蛋白表达。

精神分裂症的病理生理学包括神经传递改变、细胞内信号通路活性失调和导致突触可塑性缺陷的异常树突形态。这些过程都需要细胞膜上的动态蛋白质-蛋白质相互作用。脂质修饰通过添加脂肪酸或异戊二烯基部分增加底物疏水性将蛋白质靶向膜，最近的证据表明失调的翻译后脂质修饰可能在包括精神分裂症在内的多种神经精神疾病中起作用。与这些新发现一致，我们最近报道了精神分裂症中蛋白质 S-棕榈酰化降低。蛋白质异戊二烯化是在许多蛋白质底物上发生在 S-棕榈酰化上游的脂质修饰，促进关键细胞内信号蛋白的膜定位和活性。因此，我们假设，除了棕榈酰化外，蛋白质异戊二烯化在精神分裂症中可能是异常的。为了测试这一点，我们检测了精神分裂症患者和配对比较受试者（n = 13 对）死后背外侧前额叶皮层中五个异戊二烯基转移酶亚基（FNTA、FNTB、PGGT1B、RABGGTA 和 RABGGTB）的蛋白质表达。我们发现精神分裂症患者的 FNTA (14%)、PGGT1B (13%) 和 RABGGTB (8%) 水平降低。为了确定上游或下游因素是否可能推动这些变化，我们还检测了类异戊二烯合酶 FDPS 和 GGPS1 以及异戊二烯化依赖性加工酶 RCE 和 ICMT 的蛋白质表达。我们发现这些上游和下游酶具有正常的蛋白质表达。为了排除慢性抗精神病药物治疗的影响，我们检测了长期用氟哌啶醇癸酸酯治疗的大鼠皮层中的 FNTA、PGGT1B 和 RABGGTB，发现这些蛋白质的表达没有变化。鉴于异戊二烯化在突触处发现的关键信号蛋白的定位中所起的作用，这些数据提供了精神分裂症中异常蛋白质-蛋白质相互作用和蛋白质定位的潜在机制。