Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex.,Translational Psychiatry

当前位置： X-MOL 学术 › Transl. Psychiaty › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex.
Translational Psychiatry ( IF 5.8 ) Pub Date : 2020-01-10 , DOI: 10.1038/s41398-019-0610-7
Anita L Pinner ₁ , Toni M Mueller ₁ , Khaled Alganem ₂ , Robert McCullumsmith ₂ , James H Meador-Woodruff ₁

Affiliation

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：

死后精神分裂症背外侧前额皮质中异戊二烯基转移酶亚基的蛋白质表达。

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以及导致该疾病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动态的蛋白质-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来增加底物疏水性，从而将蛋白质靶向膜，最近的证据表明，失调的翻译后脂质修饰可能在多种神经精神疾病（包括精神分裂症）中发挥作用。与这些新发现一致的是，我们最近报道了精神分裂症中蛋白质 S-棕榈酰化的减少。蛋白质异戊二烯化是一种脂质修饰，发生在许多蛋白质底物上的 S-棕榈酰化上游，促进关键细胞内信号蛋白的膜定位和活性。因此，我们假设，除了棕榈酰化之外，精神分裂症中蛋白质异戊二烯化也可能异常。为了测试这一点，我们检测了精神分裂症患者和配对对照受试者（n = 13 对）死后背外侧前额皮质中五个异戊烯基转移酶亚基（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驱动这些变化，我们还测定了类异戊二烯合酶 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。为了排除长期抗精神病药物治疗的影响，我们检测了长期接受氟哌啶醇癸酸酯治疗的大鼠皮质中的 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中发现的关键信号蛋白定位中所起的作用，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。

更新日期：2020-01-11

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11