CAG重复长度的适度减少挽救了1型脊髓角共济失调小鼠的运动缺陷,但不能挽救浦肯野细胞病理学和神经胶质瘤

Stephen Gilliat, Juao-Guilherme Rosa, Genevieve Benjamin, Kaelin Sbrocco, Wensheng Lin, Marija Cvetanovic
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引用次数: 0

摘要

脊髓角性共济失调1型(SCA1)是一种致命的、显性遗传的神经退行性疾病,由共济失调1(ATXN1)基因中CAG重复序列的扩增引起。SCA1的特征是小脑浦肯野细胞的早期和突出病理,导致平衡和协调缺陷。我们先前证明,小脑星形胶质细胞以双相、疾病依赖性阶段的方式参与SCA1的发病机制。我们发现星形胶质细胞中促炎转录调节因子核因子κ-活化B细胞轻链增强子(NF-κB)信号传导在早期SCA1中具有神经保护作用。在这里,我们试图检验在疾病早期进一步诱导SCA1模型小鼠星形胶质细胞中的NF-κB活化是否具有治疗益处。为了完成这项任务,我们创建了一种新的Slc1a3-CreERT/IKKβCA/ATXN1[82Q]三重转基因小鼠模型,在该模型中,4周龄时注射TMX可导致组成型活性κB激酶β抑制剂(IKKβCA)的表达,IKKβ是NF-κB信号传导的主要激活剂。当我们评估SCA1样表型时,我们注意到ATXN1[82Q]小鼠不再表现出运动缺陷,即使在疾病的晚期也是如此。我们对突变体ATXN1基因进行了测序,发现CAG重复数已从82个减少到71个。然而,尽管运动表型丧失,但在ATXN1[71Q]小鼠中仍然可以检测到其他特征明确的SCA1变化,包括浦肯野细胞树突萎缩、小脑星形胶质细胞增生和小胶质细胞增生的特征,以及浦肯野细胞病相关基因表达变化。我们发现,在星形胶质细胞中表达IKKβCA的SCA1小鼠中,PC延迟萎缩和钙结合蛋白减少,提示NF-κB信号传导增加对浦肯野细胞病理的有益作用。CAG降低的SCA1小鼠运动表型的变化使我们无法评估IKKβCA对这些小鼠运动缺陷的神经保护潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Modest Reduction in CAG Repeat Length Rescues Motor Deficits but Not Purkinje Cell Pathology and Gliosis in Spinocerebellar Ataxia Type 1 Mice
Spinocerebellar ataxia type 1 (SCA1) is a fatal, dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by the early and prominent pathology of the cerebellar Purkinje cells that results in balance and coordination deficits. We previously demonstrated that cerebellar astrocytes contribute to SCA1 pathogenesis in a biphasic, stage of disease-dependent manner. We found that pro-inflammatory transcriptional regulator nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling in astrocytes has a neuroprotective role during early-stage SCA1. Here, we sought to examine whether further inducing NF-κB activation in astrocytes of SCA1 model mice at an early stage of the disease has therapeutic benefits. To perform this task, we created a novel Slc1a3-CreERT/IKKβCA/ATXN1[82Q] triple transgenic mouse model in which TMX injection at 4 weeks of age results in the expression of constitutively active inhibitor of kB kinase beta (IKKβCA), the main activator of NF-κB signaling. As we evaluated SCA1-like phenotypes, we noticed that ATXN1[82Q] mice did not exhibit motor deficits anymore, even at very late stages of the disease. We sequenced the mutant ATXN1 gene and discovered that the CAG repeat number had decreased from 82 to 71. However, despite the loss of motor phenotype, other well-characterized SCA1-changes, including atrophy of Purkinje cell dendrites, hallmarks of cerebellar astrogliosis and microgliosis, and Purkinje cell disease-associated gene expression changes, were still detectable in ATXN1[71Q] mice. We found delayed PC atrophy and calbindin reduction in SCA1 mice expressing IKKβCA in astrocytes implicating beneficial effects of increased NF-κB signaling on Purkinje cell pathology. The change in the motor phenotype of SCA1 mice with CAG reduction prevented us from evaluating the neuroprotective potential of IKKβCA on motor deficits in these mice.
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