Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons
Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons
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DOI：
10.1038/nn1876
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发表时间：
2007-05-01
影响因子：
25
通讯作者：
Przedborski, Serge
中科院分区：
文献类型：
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作者：
Nagai, Makiko;Re, Diane B.;Przedborski, Serge
超氧化物歧化酶-1（SOD 1）的突变可能通过细胞自主和非细胞自主过程的组合导致一种形式的致命麻痹性疾病肌萎缩性侧索硬化症（ALS）。在这里，我们表明突变的人SOD 1在原代小鼠脊髓运动神经元中的表达不会引起运动神经元变性。相反，表达突变的SOD 1的啮齿动物星形胶质细胞杀死脊髓原代和胚胎小鼠干细胞衍生的运动神经元。这是由可溶性毒性因子通过Bax依赖性机制触发的。然而，突变的星形胶质细胞不引起脊髓GABA能或背根神经节神经元或胚胎干细胞衍生的中间神经元的死亡。与星形胶质细胞相反，表达突变SOD 1的成纤维细胞、小胶质细胞、皮质神经元和肌细胞不会引起明显的神经毒性。这些结果表明，星形胶质细胞可能在ALS的脊髓运动神经元的特异性变性中发挥作用。星形胶质细胞衍生的可溶性因子的鉴定可能从致病和治疗的角度对ALS具有深远的意义。
Mutations in superoxide dismutase-1 ( SOD1) cause a form of the fatal paralytic disorder amyotrophic lateral sclerosis ( ALS), presumably by a combination of cell-autonomous and non - cell- autonomous processes. Here, we show that expression of mutated human SOD1 in primary mouse spinal motor neurons does not provoke motor neuron degeneration. Conversely, rodent astrocytes expressing mutated SOD1 kill spinal primary and embryonic mouse stem cell - derived motor neurons. This is triggered by soluble toxic factor( s) through a Bax- dependent mechanism. However, mutant astrocytes do not cause the death of spinal GABAergic or dorsal root ganglion neurons or of embryonic stem cell - derived interneurons. In contrast to astrocytes, fibroblasts, microglia, cortical neurons and myocytes expressing mutated SOD1 do not cause overt neurotoxicity. These findings indicate that astrocytes may play a role in the specific degeneration of spinal motor neurons in ALS. Identification of the astrocyte- derived soluble factor( s) may have far- reaching implications for ALS from both a pathogenic and therapeutic standpoint.