Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity.
Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity.
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DOI：
10.1523/jneurosci.3994-09.2010
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发表时间：
2010-04-21
期刊：
影响因子：
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通讯作者：
Gutmann DH
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文献类型：
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作者：
Brown JA;Gianino SM;Gutmann DH
患有神经纤维瘤病-1（NF 1）遗传性癌症综合征的个体表现出主要影响中枢神经系统（CNS）的神经元功能障碍。在这份报告中，我们证明了一个独特的脆弱性中枢神经系统神经元，但不是周围神经系统（PNS）神经元，减少NF 1基因表达。与背根神经节神经元不同，与野生型神经元相比，Nf 1杂合（Nf 1 +/−）海马和视网膜神经节细胞（RGC）神经元的生长锥面积和轴突长度减少，凋亡增加。这些异常的Nf 1 +/− CNS神经元表型并不反映Ras通路的过度活化，而是由受损的神经纤维蛋白介导的cAMP生成引起的。在这方面，用毛喉素或咯利普兰处理而不是MEK或PI 3-K抑制升高cAMP水平，在体外将这些异常逆转至野生型水平。此外，Nf 1 +/− CNS（而非PNS）神经元在体外对兴奋性毒性或氧化应激的反应中表现出凋亡增加。由于儿童与NF 1相关的视神经胶质瘤往往发展视力丧失和NF 1基因工程小鼠与视神经胶质瘤表现出RGC神经元凋亡在体内，我们进一步证明，RGC凋亡导致视神经胶质瘤在NF 1基因工程小鼠是衰减咯利普兰治疗在体内。与视神经胶质瘤诱导的RGC细胞凋亡相似，在视神经挤压损伤后Nf 1 +/−小鼠中增加的RGC神经元死亡也被体内咯利普兰治疗减弱。总之，这些研究结果建立了一个独特的作用，神经纤维蛋白在中枢神经系统神经元的脆弱性损伤，定义了一个中枢神经系统特异性神经纤维蛋白细胞内信号通路负责神经元的生存，并奠定了基础，为未来的神经保护性胶质瘤治疗方法。
Individuals with the Neurofibromatosis-1 (NF1) inherited cancer syndrome exhibit neuronal dysfunction that predominantly affects the central nervous system (CNS). In this report, we demonstrate a unique vulnerability of CNS neurons, but not peripheral nervous system (PNS) neurons, to reduced Nf1 gene expression. Unlike dorsal root ganglion neurons, Nf1 heterozygous (Nf1+/−) hippocampal and retinal ganglion cell (RGC) neurons have decreased growth cone areas and neurite lengths, and increased apoptosis compared to their wild-type counterparts. These abnormal Nf1+/− CNS neuronal phenotypes do not reflect Ras pathway hyperactivation, but rather result from impaired neurofibromin-mediated cAMP generation. In this regard, elevating cAMP levels with forskolin or rolipram treatment, but not MEK or PI3-K inhibition, reverses these abnormalities to wild-type levels in vitro. In addition, Nf1+/− CNS, but not PNS, neurons exhibit increased apoptosis in response to excitotoxic or oxidative stress in vitro. Since children with NF1-associated optic gliomas often develop visual loss and Nf1 genetically-engineered mice with optic glioma exhibit RGC neuronal apoptosis in vivo, we further demonstrate that RGC apoptosis resulting from optic glioma in Nf1 genetically-engineered mice is attenuated by rolipram treatment in vivo. Similar to optic glioma-induced RGC apoptosis, the increased RGC neuronal death in Nf1+/− mice following optic nerve crush injury is also attenuated by rolipram treatment in vivo. Together, these findings establish a distinctive role for neurofibromin in CNS neurons with respect to vulnerability to injury, define a CNS-specific neurofibromin intracellular signaling pathway responsible for neuronal survival, and lay the foundation for future neuroprotective glioma treatment approaches.