Zlatic Stephanie A, Duong Duc, Gadalla Kamal K E, Murage Brenda, Ping Lingyan, Shah Ruth, Fink James J, Khwaja Omar, Swanson Lindsay C, Sahin Mustafa, Rayaprolu Sruti, Kumar Prateek, Rangaraju Srikant, Bird Adrian, Tarquinio Daniel, Carpenter Randall, Cobb Stuart, Faundez Victor
Departments of Cell Biology, Emory University, Atlanta, GA 30322, USA.
Departments of Biochemistry, Emory University, Atlanta, GA 30322, USA.
iScience. 2022 Aug 17;25(9):104966. doi: 10.1016/j.isci.2022.104966. eCollection 2022 Sep 16.
MECP2 loss-of-function mutations cause Rett syndrome, a neurodevelopmental disorder resulting from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome of Rett cerebrospinal fluid (CSF) to identify consensus Rett proteome and ontologies shared across three species. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, synapse compartments, and the neurosecretory protein VGF. We used shared Rett ontologies to select analytes for orthogonal quantification and functional validation. VGF and ontologically selected CSF proteins had genotypic discriminatory capacity as determined by receiver operating characteristic analysis in and Differentially expressed CSF proteins distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that mutant CSF proteomes and ontologies inform putative mechanisms and biomarkers of disease. We suggest that Rett syndrome results from synapse and metabolism dysfunction.
MECP2功能丧失突变会导致雷特综合征，这是一种由大脑转录组紊乱引起的神经发育障碍。这些转录缺陷如何转化为疾病蛋白质组仍然未知。我们研究了雷特脑脊液（CSF）的蛋白质组，以确定三种物种共有的雷特蛋白质组和本体。雷特CSF蛋白质组富集了注释为高密度脂蛋白、补体、线粒体、柠檬酸/丙酮酸代谢、突触区室和神经分泌蛋白VGF的蛋白质。我们使用共享的雷特本体来选择用于正交定量和功能验证的分析物。VGF和本体选择的CSF蛋白具有基因型鉴别能力，这是通过在[具体内容1]和[具体内容2]中的受试者工作特征分析确定的。差异表达的CSF蛋白将雷特综合征与相关神经发育障碍——CDKL5缺乏症区分开来。我们提出，突变的CSF蛋白质组和本体为疾病的推定机制和生物标志物提供了信息。我们认为雷特综合征是由突触和代谢功能障碍引起的。
