Macopson-Jones Joshua G, Adams Maile, Philippe Julien, La Spada Albert R
Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, United States.
Department of Neurology, Duke University School of Medicine, Durham, NC, United States.
Front Mol Neurosci. 2024 Nov 22;17:1478110. doi: 10.3389/fnmol.2024.1478110. eCollection 2024.
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder characterized by cerebellar and retinal degeneration. SCA7 is caused by a CAG-polyglutamine repeat expansion in the ataxin-7 gene, which encodes a transcription factor protein that is a core component of the STAGA co-activator complex. As ataxin-7 protein regularly shuttles between the nucleus and the cytosol, we sought to test if polyglutamine-expanded ataxin-7 protein results in nuclear membrane abnormalities or defects in nucleocytoplasmic (N/C) transport.
We used SCA7 266Q knock-in mice and their wild-type (WT) littermate controls to assess nuclear membrane morphology and N/C transport. Additionally, induced pluripotent stem cells (iPSCs) from SCA7 patients were differentiated into neural progenitor cells (NPCs) and cortical neurons to measure nuclear import and export dynamics. The expression of nucleoporin POM121, a key regulator of N/C transport, was also analyzed in SCA7-derived NPCs.
Our analysis revealed no significant differences in nuclear membrane morphology between SCA7 knock-in mice and WT controls, nor did we observe alterations in N/C transport within neurons from these mice. However, we documented significantly increased nuclear import in both NPCs and cortical neurons derived from SCA7 patient iPSCs. When we examined nuclear export function in SCA7 iPSC-derived cortical neurons, we noted a modest decrease that constituted only a trend. Furthermore, we identified a significant decrease in the expression of full-length POM121 in SCA7 NPCs.
Our results reveal evidence for altered N/C transport in SCA7. The reduction in POM121 expression suggests a potential mechanism underlying these transport abnormalities. Importantly, our data suggests the N/C transport defect in SCA7 is distinctly different from other related neurodegenerative disorders.
7型脊髓小脑共济失调（SCA7）是一种遗传性神经退行性疾病，其特征为小脑和视网膜变性。SCA7由ataxin-7基因中的CAG-多聚谷氨酰胺重复序列扩增引起，该基因编码一种转录因子蛋白，它是STAGA共激活复合物的核心成分。由于ataxin-7蛋白经常在细胞核和细胞质之间穿梭，我们试图测试多聚谷氨酰胺扩增的ataxin-7蛋白是否会导致核膜异常或核质（N/C）转运缺陷。
我们使用SCA7 266Q基因敲入小鼠及其野生型（WT）同窝对照来评估核膜形态和N/C转运。此外，将SCA7患者的诱导多能干细胞（iPSC）分化为神经祖细胞（NPC）和皮质神经元，以测量核输入和输出动力学。还在源自SCA7的NPC中分析了N/C转运的关键调节因子核孔蛋白POM121的表达。
我们的分析显示，SCA7基因敲入小鼠和WT对照之间的核膜形态没有显著差异，我们也未观察到这些小鼠神经元内N/C转运的改变。然而，我们记录到源自SCA7患者iPSC的NPC和皮质神经元中的核输入均显著增加。当我们检查SCA7 iPSC衍生的皮质神经元中的核输出功能时，我们注意到有适度下降，仅构成一种趋势。此外，我们发现SCA7 NPC中全长POM121的表达显著降低。
我们的结果揭示了SCA7中N/C转运改变的证据。POM121表达的降低表明了这些转运异常的潜在机制。重要的是，我们的数据表明SCA7中的N/C转运缺陷与其他相关神经退行性疾病明显不同。
