Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice
Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice
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DOI：
10.1073/pnas.0813339106
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发表时间：
2009-03-17
影响因子：
11.1
通讯作者：
Cleveland, Don W.
中科院分区：
文献类型：
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作者：
Lobsiger, Christian S.;Boillee, Severine;Cleveland, Don W.
ALS的遗传形式中的神经变性是非细胞自主的，ALS引起的突变SOD 1损伤在多种细胞类型中发展。运动神经元内广泛表达的突变型SOD 1基因的选择性失活已经证明，运动神经元内的突变型损伤是疾病起始的决定因素，而邻近星形胶质细胞或小胶质细胞内的突变型合成加速疾病进展。我们现在报告了一个令人惊讶的发现，即在雪旺细胞内完全歧化酶活性ALS连锁突变体（SOD 1（G37 R））的合成减少（70%）显着加速疾病进展，伴随着神经中胰岛素样生长因子1（IGF-1）的减少。再加上较短的疾病持续时间在小鼠模型中引起的歧化酶活性与歧化酶活性的SOD 1突变体，我们的研究结果牵连在疾病进展过程中的氧化级联反应，在轴突鞘雪旺细胞内触发，可以改善歧化酶活性升高。因此，在ALS的家族性形式中，歧化酶活性突变体SOD 1的治疗性下调应远离雪旺细胞。
Neurodegeneration in an inherited form of ALS is non-cell-autonomous, with ALS-causing mutant SOD1 damage developed within multiple cell types. Selective inactivation within motor neurons of an ubiquitously expressed mutant SOD1 gene has demonstrated that mutant damage within motor neurons is a determinant of disease initiation, whereas mutant synthesis within neighboring astrocytes or microglia accelerates disease progression. We now report the surprising finding that diminished synthesis (by 70%) within Schwann cells of a fully dismutase active ALS-linked mutant (SOD1(G37R)) significantly accelerates disease progression, accompanied by reduction of insulin-like growth factor 1 (IGF-1) in nerves. Coupled with shorter disease duration in mouse models caused by dismutase inactive versus dismutase active SOD1 mutants, our findings implicate an oxidative cascade during disease progression that is triggered within axon ensheathing Schwann cells and that can be ameliorated by elevated dismutase activity. Thus, therapeutic down-regulation of dismutase active mutant SOD1 in familial forms of ALS should be targeted away from Schwann cells.