Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 (G93A) mouse model of amyotrophic lateral sclerosis.
Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 (G93A) mouse model of amyotrophic lateral sclerosis.
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DOI：
10.3389/fncel.2015.00410
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发表时间：
2015
影响因子：
5.3
通讯作者：
Shaw PJ
中科院分区：
文献类型：
--
作者：
Baker DJ;Blackburn DJ;Keatinge M;Sokhi D;Viskaitis P;Heath PR;Ferraiuolo L;Kirby J;Shaw PJ
星形胶质细胞在肌萎缩性侧索硬化症（ALS）的进展中起关键作用。此前，ALS SOD1G93A模型症状前阶段星形胶质细胞的基因表达谱显示乳酸代谢减少和营养支持改变。在这里，我们通过激光捕获显微解剖（LCM）从SOD1G93A小鼠腰椎脊髓分离出有症状和晚期疾病的星形胶质细胞，对其进行了微阵列分析，以完成整个疾病过程中星形胶质细胞行为的图像。有症状和晚期疾病的星形胶质细胞表现出明显的转录本上调，这些转录本定义了反应性表型，例如那些参与溶酶体和吞噬途径的转录本。脊髓己糖氨酸酶B酶活性和星形细胞吞噬能力的功能分析表明，SOD1G93A与同窝对照相比，溶酶体酶活性和吞噬活性显著增加，验证了微阵列研究的结果。除了在这两个阶段看到的反应性增加外，晚期疾病的星形胶质细胞显示许多参与胆固醇稳态的转录物表达减少。对胆固醇合成的主要调节因子SREBP2的染色显示，在晚期SOD1G93A脊髓中，星形细胞和运动神经元的细胞质定位增加，表明转录本的下调可能是由于晚期疾病期间中枢神经系统中胆固醇过量，可能是由于神经元碎片的吞噬。我们的数据显示，在ALS疾病进展过程中，SOD1G93A星形胶质细胞的特征更多的是支持功能的丧失，而不是毒性表型，未来的研究应侧重于恢复性治疗。
Astrocytes are key players in the progression of amyotrophic lateral sclerosis (ALS). Previously, gene expression profiling of astrocytes from the pre-symptomatic stage of the SOD1G93A model of ALS has revealed reduced lactate metabolism and altered trophic support. Here, we have performed microarray analysis of symptomatic and late-stage disease astrocytes isolated by laser capture microdissection (LCM) from the lumbar spinal cord of the SOD1G93A mouse to complete the picture of astrocyte behavior throughout the disease course. Astrocytes at symptomatic and late-stage disease show a distinct up-regulation of transcripts defining a reactive phenotype, such as those involved in the lysosome and phagocytic pathways. Functional analysis of hexosaminidase B enzyme activity in the spinal cord and of astrocyte phagocytic ability has demonstrated a significant increase in lysosomal enzyme activity and phagocytic activity in SOD1G93A vs. littermate controls, validating the findings of the microarray study. In addition to the increased reactivity seen at both stages, astrocytes from late-stage disease showed decreased expression of many transcripts involved in cholesterol homeostasis. Staining for the master regulator of cholesterol synthesis, SREBP2, has revealed an increased localization to the cytoplasm of astrocytes and motor neurons in late-stage SOD1G93A spinal cord, indicating that down-regulation of transcripts may be due to an excess of cholesterol in the CNS during late-stage disease possibly due to phagocytosis of neuronal debris. Our data reveal that SOD1G93A astrocytes are characterized more by a loss of supportive function than a toxic phenotype during ALS disease progression and future studies should focus upon restorative therapies.