Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Italy.
Brain. 2013 Sep;136(Pt 9):2859-75. doi: 10.1093/brain/awt215.
Globoid cell leukodystrophy (Krabbe disease) is a neurological disorder of infants caused by genetic deficiency of the lysosomal enzyme β-galactosylceramidase leading to accumulation of the neurotoxic metabolite 1-β-d-galactosylsphingosine (psychosine) in the central nervous system. Angiogenesis plays a pivotal role in the physiology and pathology of the brain. Here, we demonstrate that psychosine has anti-angiogenic properties by causing the disassembling of endothelial cell actin structures at micromolar concentrations as found in the brain of patients with globoid cell leukodystrophy. Accordingly, significant alterations of microvascular endothelium were observed in the post-natal brain of twitcher mice, an authentic model of globoid cell leukodystrophy. Also, twitcher endothelium showed a progressively reduced capacity to respond to pro-angiogenic factors, defect that was corrected after transduction with a lentiviral vector harbouring the murine β-galactosylceramidase complementary DNA. Finally, RNA interference-mediated β-galactosylceramidase gene silencing causes psychosine accumulation in human endothelial cells and hampers their mitogenic and motogenic response to vascular endothelial growth factor. Accordingly, significant alterations were observed in human microvasculature from brain biopsy of a globoid cell leukodystrophy case. Together these data demonstrate that β-galactosylceramidase deficiency induces significant alterations in endothelial neovascular responses that may contribute to central nervous system and systemic damages that occur in globoid cell leukodystrophy.
球形细胞脑白质营养不良（Krabbe 病）是一种婴儿神经发育障碍，由溶酶体酶β-半乳糖苷酰鞘氨醇酶的遗传缺陷引起，导致神经毒性代谢物 1-β-d-半乳糖基鞘氨醇（神经鞘氨醇）在中枢神经系统中积累。血管生成在大脑的生理和病理中起着关键作用。在这里，我们证明神经鞘氨醇具有抗血管生成特性，因为它在患者大脑中发现的微摩尔浓度下导致内皮细胞肌动蛋白结构解体球状细胞脑白质营养不良。因此，在 twitcher 小鼠的出生后大脑中观察到微血管内皮的显着变化，这是球状细胞脑白质营养不良的真实模型。此外，twitcher 内皮表现出对促血管生成因子的反应能力逐渐降低的缺陷，在用携带小鼠β-半乳糖苷酰鞘氨醇酶 cDNA 的慢病毒载体转导后得到纠正。最后，RNA 干扰介导的β-半乳糖苷酰鞘氨醇酶基因沉默导致人内皮细胞中神经鞘氨醇的积累，并阻碍它们对血管内皮生长因子的有丝分裂和趋化运动反应。因此，在球状细胞脑白质营养不良病例的脑活检中观察到人类微血管发生显着变化。这些数据共同表明，β-半乳糖苷酰鞘氨醇酶缺乏会导致内皮新生血管反应的显着变化，这可能导致发生在球形细胞脑白质营养不良中的中枢神经系统和全身损伤。
