Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease.
Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease.
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骨髓移植可纠正溶酶体贮积症中枢神经系统神经元的酶缺陷。
DOI：
10.1073/pnas.91.8.2970
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发表时间：
1994
影响因子：
11.1
通讯作者：
Wurzelmann,S
中科院分区：
文献类型：
--
作者：
Walkley,SU;Thrall,MA;Dobrenis,K;Huang,M;March,PA;Siegel,DA;Wurzelmann,S
神经元贮积症是人类和动物的致命性神经退行性疾病，其由溶酶体水解酶活性的遗传缺陷引起。受影响的个体通常在出生时表现正常，但最终发展为进行性神经系统症状，包括感觉和运动缺陷、智力迟钝和癫痫发作。我们已经研究了骨髓移植作为酶替代的一种手段的有效性，使用猫与溶酶体贮积病α-甘露糖苷。接受治疗的动物在移植后1-2年表现出很少或没有神经系统体征的进展，而未接受治疗的猫在6个月大时变得严重受损并达到终末期疾病。在给药动物的脑组织中发现溶酶体α-甘露糖苷酶活性增加，电子显微镜检查显示大多数神经元内没有溶酶体储存的证据。酸性α-D-甘露糖苷甘露水解酶（EC 3.2. 1.24），使用5-溴-4-氯-3-吲哚基α-D-甘露聚糖苷，表明功能酶存在于神经元、神经胶质细胞和与血管相关的细胞中。这项研究提供了直接的证据，骨髓移植作为治疗神经元贮积病可以导致显着水平的缺失溶酶体水解酶的中枢神经系统的神经元内，并补偿遗传代谢缺陷。
Neuronal storage disorders are fatal neurodegenerative diseases of humans and animals that are caused by inherited deficiencies of lysosomal hydrolase activity. Affected individuals often appear normal at birth but eventually develop progressive neurologic symptoms including sensory and motor deficits, mental retardation, and seizures. We have examined efficacy of bone marrow transplantation as a means of enzyme replacement, using cats with the lysosomal storage disease alpha-mannosidosis. Treated animals showed little or no progression of neurologic signs 1-2 years after transplant, whereas untreated cats became severely impaired and reached endstage disease by 6 months of age. Increased lysosomal alpha-mannosidase activity was found in brain tissue of the treated animals, and electron microscopy revealed no evidence of lysosomal storage within most neurons. Histochemical localization of acidic alpha-D-mannoside mannohydrolase (EC 3.2. 1.24), using 5-bromo-4-chloro-3-indolyl alpha-D-mannopyranoside, showed that functional enzyme was present in neurons, glial cells, and cells associated with blood vessels. This study provides direct evidence that bone marrow transplantation as treatment for a neuronal storage disease can lead to significant levels of a missing lysosomal hydrolase within neurons of the central nervous system and to compensation for the genetic metabolic defect.