Biochemical and pathological evaluation of long-lived mice with globoid cell leukodystrophy after bone marrow transplantation
Biochemical and pathological evaluation of long-lived mice with globoid cell leukodystrophy after bone marrow transplantation
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DOI：
10.1016/j.ymgme.2005.06.023
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发表时间：
2005-09-01
影响因子：
3.8
通讯作者：
Wenger, DA
中科院分区：
文献类型：
--
作者：
Luzi, P;Rafi, MA;Wenger, DA
球样细胞脑白质营养不良（GLD）是一种由溶酶体酶半乳糖苷酶（GALC）缺乏引起的中枢和外周神经系统疾病。与该疾病相关的病理变化包括球状细胞的积累和由于产生psychosine（一种负责少突胶质细胞凋亡的毒性代谢物）导致的髓鞘损失。虽然大多数患者在6个月大之前出现症状，但老年患者也被诊断出来。此时的治疗仅限于无症状和迟发性患者的造血干细胞移植。GLD在几种动物物种中自然发生，包括小鼠，狗和猴子。此外，在我们的实验室中产生了GLD的转基因（its）小鼠模型。Trs小鼠出现症状的速度比ticker小鼠慢，平均存活时间长10天。在这项研究中，我们评估了骨髓移植（BMT）的治疗效果使用trs小鼠。BMT延长了一些治疗动物的寿命超过一年。骨髓移植后，大脑中GALC活性达到正常值的15-20%，肝脏和坐骨神经中GALC活性接近正常值。在长寿命的移植动物中，精神病碱的水平在大脑中正常化，在坐骨神经中大大降低。脑切片染色显示髓鞘更丰富，质量更好，几乎没有球状细胞。坐骨神经的电子显微镜照片显示神经内膜水肿减少，轴突密度增加，以及与髓鞘再生轴突相关的丰富的洋葱球结构。因此，BMT可以改善GLD的许多生化和病理特征。然而，可能需要额外的治疗来完全纠正这种疾病的特征。(c)2005年爱思唯尔公司All rights reserved.
Globoid cell leukodystrophy (GLD) is a disorder of the central and peripheral nervous systems caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). The pathological changes associated with the disease include accumulation of globoid cells and loss of myelin due to production of psychosine, a toxic metabolite responsible for the apoptosis of oligodendrocytes. While most patients present with symptoms before 6 months of age, older patients are also diagnosed. Treatment at this time is limited to hematopoietic stem cell transplantation in asymptomatic and late-onset patients. GLD occurs naturally in several animal species including mice, dogs, and monkeys. In addition, a transgenic (its) mouse model of GLD was generated in our laboratory. Trs mice develop symptoms slower than twitcher mice and survive an average of 10 days longer. In this study, we evaluated the therapeutic effects of bone marrow transplantation (BMT) using trs mice. BMT prolonged the life of some treated animals to over one year. After BMT, GALC activity reached 15-20% of normal in brain and near normal values in liver and sciatic nerve. In long-lived transplanted animals psychosine levels were normalized in the brain and greatly reduced in the sciatic nerve. Staining of brain sections showed more abundant and better quality myelin and near absence of globoid cells. Electron micrographs of sciatic nerves showed reduced endoneurial edema, increased axon density, and abundant onion bulb structures associated with remyelinating axons. Therefore, BMT can ameliorate many of the biochemical and pathological features of GLD. However, additional therapies may be required to completely correct the features of this disease. (c) 2005 Elsevier Inc. All rights reserved.