The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis.
The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis.
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DOI：
10.1523/jneurosci.3579-11.2011
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发表时间：
2011-10-26
期刊：
影响因子：
--
通讯作者：
Sands MS
中科院分区：
文献类型：
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作者：
Macauley SL;Pekny M;Sands MS
婴儿神经元蜡样脂褐质沉积症（INCL）是一种影响婴儿期中枢神经系统的遗传性神经退行性疾病。 INCL 是由 CLN1 基因突变导致溶酶体水解酶棕榈酰蛋白硫酯酶 (PPT1) 缺陷引起的。 INCL 的小鼠模型，即 PPT1−/− 小鼠，是人类疾病的准确表型。在 PPT1−/− 大脑中观察到的第一个病理变化是 GFAP 上调的区域，这预示着未来神经退行性病变的区域。我们假设阻止反应性星形胶质细胞中 GFAP 上调将改变中枢神经系统疾病。为了验证这一假设，我们培育了同时携带 GFAP、Vimentin 和 PPT1 基因无效突变的小鼠 (GFAP−/−Vimentin−/−PPT1−/−)。尽管GFAP−/−Vim−/−PPT1−/−小鼠的临床和病理特征与INCL相似，但疾病出现更早，进展更快。这种加速表型的潜在机制之一是中枢神经系统内深刻的神经炎症反应。因此，我们的数据确定了慢性神经变性模型 INCL 中星形胶质细胞激活过程中中间丝上调的保护作用。
Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative disorder affecting the CNS during infancy. INCL is caused by mutations in the CLN1 gene that leads to a deficiency in the lysosomal hydrolase, palmitoyl protein thioesterase (PPT1). A murine model of INCL, the PPT1−/− mouse, is an accurate phenocopy of the human disease. The first pathological change observed in the PPT1−/− brain is regional areas of GFAP upregulation, which predicts future areas of neurodegeneration. We hypothesized that preventing GFAP upregulation in reactive astrocytes will alter the CNS disease. To test this hypothesis, we generated mice simultaneously carrying null mutations in the GFAP, Vimentin, and PPT1 genes (GFAP−/−Vimentin−/−PPT1−/−). Although the clinical and pathological features of the GFAP−/−Vim−/−PPT1−/− mice are similar to INCL, the disease appears earlier and progresses more rapidly. One mechanism underlying this accelerated phenotype is a profound neuroinflammatory response within the CNS. Thus, our data identify a protective role for intermediate filament upregulation during astrocyte activation in INCL, a model of chronic neurodegeneration.