Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection
Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection
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DOI：
10.1093/brain/awq167
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发表时间：
2010-08-01
期刊：
影响因子：
14.5
通讯作者：
Isacson, Ole
中科院分区：
文献类型：
--
作者：
Hedlund, Eva;Karlsson, Martin;Isacson, Ole
不同的体细胞运动神经元亚群在肌萎缩侧索硬化症、脊髓性肌萎缩症和脊髓延髓肌萎缩症等疾病中表现出不同的退化脆弱性。对突变型超氧化物歧化酶 1 过度表达的肌萎缩侧索硬化症模型小鼠的研究表明，疾病的起始是运动神经元固有的，而星形胶质细胞和小胶质细胞则促进疾病的进展。因此，对运动神经元疾病中表现出不同的退化脆弱性的运动神经元的正常转录谱进行分析，可以为相对脆弱性的机制提供重要线索。通过激光捕获显微切割从正常大鼠的三个解剖核、动眼神经/滑车（脑神经 3/4）、舌下神经（脑神经 12）和颈脊髓的侧运动柱中分离出运动神经元的整体基因表达谱，显示出运动神经元疾病中对退化的不同脆弱性，确定了每个神经元亚群的丰富转录本。内质网和线粒体功能、泛素化、细胞凋亡调节、氮代谢、钙调节、运输、生长和RNA加工等相关基因的调控存在显着差异；与运动神经元疾病有关的细胞途径。对具有直接生物学意义的基因的确认确定了胰岛素样生长因子 II、鸟嘌呤脱氨酶、外周蛋白、早期生长反应 1、可溶性鸟苷酸环化酶 1A3 和胎盘生长因子蛋白的差异定位。此外，脑神经 3/4 限制基因胰岛素样生长因子 II 和鸟嘌呤脱氨酶保护脊髓运动神经元免受谷氨酸诱导的毒性（P < 0.001，方差分析），表明我们的方法可以识别保护或使神经元更容易退化的因素。
Different somatic motor neuron subpopulations show a differential vulnerability to degeneration in diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and spinobulbar muscular atrophy. Studies in mutant superoxide dismutase 1 over-expressing amyotrophic lateral sclerosis model mice indicate that initiation of disease is intrinsic to motor neurons, while progression is promoted by astrocytes and microglia. Therefore, analysis of the normal transcriptional profile of motor neurons displaying differential vulnerability to degeneration in motor neuron disease could give important clues to the mechanisms of relative vulnerability. Global gene expression profiling of motor neurons isolated by laser capture microdissection from three anatomical nuclei of the normal rat, oculomotor/trochlear (cranial nerve 3/4), hypoglossal (cranial nerve 12) and lateral motor column of the cervical spinal cord, displaying differential vulnerability to degeneration in motor neuron disorders, identified enriched transcripts for each neuronal subpopulation. There were striking differences in the regulation of genes involved in endoplasmatic reticulum and mitochondrial function, ubiquitination, apoptosis regulation, nitrogen metabolism, calcium regulation, transport, growth and RNA processing; cellular pathways that have been implicated in motor neuron diseases. Confirmation of genes of immediate biological interest identified differential localization of insulin-like growth factor II, guanine deaminase, peripherin, early growth response 1, soluble guanylate cyclase 1A3 and placental growth factor protein. Furthermore, the cranial nerve 3/4-restricted genes insulin-like growth factor II and guanine deaminase protected spinal motor neurons from glutamate-induced toxicity (P < 0.001, ANOVA), indicating that our approach can identify factors that protect or make neurons more susceptible to degeneration.