Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
PLoS One. 2015 Apr 7;10(4):e0121464. doi: 10.1371/journal.pone.0121464. eCollection 2015.
Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes. Lipid rafts are specialized regions of the plasma membrane, enriched in cholesterol and glycosphingolipids, involved in regulation of intracellular signaling. Among transcripts targeted by FMRP, a subset encodes proteins involved in lipid biosynthesis and homeostasis, dysregulation of which could affect the integrity and function of lipid rafts. Using a quantitative mass spectrometry-based approach we analyzed the lipid raft proteome of Fmr1 knockout mice, an animal model of Fragile X syndrome, and identified candidate proteins that are differentially represented in Fmr1 knockout mice lipid rafts. Furthermore, network analysis of these candidate proteins reveals connectivity between them and predicts functional connectivity with genes encoding components of myelin sheath, axonal processes and growth cones. Our findings provide insight to aid identification of molecular and cellular dysfunctions arising from Fmr1 silencing and for uncovering shared pathologies between Fragile X syndrome and other autism spectrum disorders.
脆性 X 综合征是遗传性智力障碍和自闭症的主要病因，它源于编码 RNA 结合蛋白脆性 X 智力低下蛋白 (FMRP) 的 FMR1 基因的转录沉默。FMRP 通过调节 mRNA 运输、稳定性和翻译的作用，调节大约 4%的脑转录物的表达，从而为其对神经元和大脑回路功能的潜在多效性效应提供了分子基础。在没有 FMRP 的情况下，几种细胞内信号通路失调，这表明细胞缺陷可能很广泛，并可能导致体内平衡的变化。脂筏是富含胆固醇和糖脂的质膜的特化区域，参与调节细胞内信号。在受 FMRP 靶向的转录物中，有一部分编码参与脂质生物合成和动态平衡的蛋白质，其失调可能会影响脂筏的完整性和功能。我们使用基于定量质谱的方法分析了脆性 X 综合征动物模型 Fmr1 敲除小鼠的脂筏蛋白质组，鉴定出了在 Fmr1 敲除小鼠脂筏中差异表达的候选蛋白。此外，对这些候选蛋白的网络分析显示它们之间存在连接性，并预测与编码髓鞘、轴突过程和生长锥成分的基因具有功能连接性。我们的发现为鉴定因 Fmr1 沉默而产生的分子和细胞功能障碍以及揭示脆性 X 综合征与其他自闭症谱系障碍之间的共同病理学提供了帮助。
