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CPT2 缺乏症在斑马鱼模型中的表现:神经发育异常、电活动、行为和与精神分裂症相关的基因表达。

CPT2 Deficiency Modeled in Zebrafish: Abnormal Neural Development, Electrical Activity, Behavior, and Schizophrenia-Related Gene Expression.

机构信息

Department of Biomedical Sciences, Creighton University, Omaha, NE 68178, USA.

Department of Biology, Creighton University, Omaha, NE 68178, USA.

出版信息

Biomolecules. 2024 Jul 26;14(8):914. doi: 10.3390/biom14080914.

Abstract

Carnitine palmitoyltransferase 2 (CPT2) is an inner mitochondrial membrane protein of the carnitine shuttle and is involved in the beta-oxidation of long chain fatty acids. Beta-oxidation provides an alternative pathway of energy production during early development and starvation. CPT2 deficiency is a genetic disorder that we recently showed can be associated with schizophrenia. We hypothesize that CPT2 deficiency during early brain development causes transcriptional, structural, and functional abnormalities that may contribute to a CNS environment that is susceptible to the emergence of schizophrenia. To investigate the effect of CPT2 deficiency on early vertebrate development and brain function, CPT2 was knocked down in a zebrafish model system. CPT2 knockdown resulted in abnormal lipid utilization and deposition, reduction in body size, and abnormal brain development. Axonal projections, neurotransmitter synthesis, electrical hyperactivity, and swimming behavior were disrupted in CPT2 knockdown zebrafish. RT-qPCR analyses showed significant increases in the expression of schizophrenia-associated genes in CPT2 knockdown compared to control zebrafish. Taken together, these data demonstrate that zebrafish are a useful model for studying the importance of beta-oxidation for early vertebrate development and brain function. This study also presents novel findings linking CPT2 deficiency to the regulation of schizophrenia and neurodegenerative disease-associated genes.

摘要

肉毒碱棕榈酰基转移酶 2(CPT2)是肉碱穿梭系统的一种线粒体内膜蛋白,参与长链脂肪酸的β氧化。β氧化在早期发育和饥饿时提供了一种替代的能量产生途径。CPT2 缺乏是一种遗传疾病,我们最近发现它可能与精神分裂症有关。我们假设 CPT2 在早期大脑发育过程中的缺乏会导致转录、结构和功能异常,这可能导致中枢神经系统环境易受精神分裂症的出现。为了研究 CPT2 缺乏对早期脊椎动物发育和大脑功能的影响,我们在斑马鱼模型系统中敲低了 CPT2。CPT2 敲低导致异常的脂质利用和沉积、体型减小以及大脑发育异常。CPT2 敲低的斑马鱼的轴突投射、神经递质合成、电过度活跃和游泳行为受到干扰。RT-qPCR 分析显示,与对照斑马鱼相比,CPT2 敲低组中与精神分裂症相关的基因表达显著增加。总之,这些数据表明,斑马鱼是研究β氧化对早期脊椎动物发育和大脑功能重要性的有用模型。这项研究还提出了新的发现,将 CPT2 缺乏与精神分裂症和神经退行性疾病相关基因的调节联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b59/11353230/99548f13539e/biomolecules-14-00914-g001.jpg

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