The ESCRT-III protein VPS4, but not CHMP4B or CHMP2B, is pathologically increased in familial and sporadic ALS neuronal nuclei.
The ESCRT-III protein VPS4, but not CHMP4B or CHMP2B, is pathologically increased in familial and sporadic ALS neuronal nuclei.
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DOI：
10.1186/s40478-021-01228-0
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发表时间：
2021-07-19
影响因子：
7.1
通讯作者：
Rothstein JD
中科院分区：
文献类型：
--
作者：
Coyne AN;Rothstein JD
核孔复合体损伤最近已成为家族性和散发性ALS疾病发病机制的早期和重要贡献者。然而，导致这种病理现象的分子事件，其特征在于减少特定的核孔蛋白从神经元核孔复合物仍然在很大程度上未知。这部分是由于缺乏有关生物学途径和蛋白质的基础核孔复合物稳态，特别是在人类神经元的知识。我们最近发现ESCRT-III蛋白CHMP 7的异常核积累在家族性和散发性ALS神经元中启动核孔复合物。在酵母和非神经元哺乳动物细胞中，CHMP 7的核重定位已显示募集ESCRT-III蛋白CHMP 4 B、CHMP 2B和VPS 4以促进核孔复合物和核膜修复和稳态。在这里，使用超分辨率结构照明显微镜，我们发现，无论是CHMP 4 B或CHMP 2B增加ALS神经元核。相比之下，在出现核孔损伤之前，VPS 4表达在ALS神经元核中以CHMP 7依赖性方式显著增加。然而，与我们先前的CHMP 7敲低研究不同，受损的VPS 4功能不会减轻NPC和整合的跨膜核孔蛋白POM 121的改变。总的来说，我们的数据表明，虽然VPS 4亚细胞定位的改变似乎与核孔复合体损伤一致，但减轻这种致病性级联反应的治疗努力应该针对上游事件，如我们先前所述的CHMP 7的核积累。在线版本包含补充材料，可通过10.1186/s40478-021-01228-0获得。
Nuclear pore complex injury has recently emerged as an early and significant contributor to familial and sporadic ALS disease pathogenesis. However, the molecular events leading to this pathological phenomenon characterized by the reduction of specific nucleoporins from neuronal nuclear pore complexes remain largely unknown. This is due in part to a lack of knowledge regarding the biological pathways and proteins underlying nuclear pore complex homeostasis specifically in human neurons. We have recently uncovered that aberrant nuclear accumulation of the ESCRT-III protein CHMP7 initiates nuclear pore complex in familial and sporadic ALS neurons. In yeast and non-neuronal mammalian cells, nuclear relocalization of CHMP7 has been shown to recruit the ESCRT-III proteins CHMP4B, CHMP2B, and VPS4 to facilitate nuclear pore complex and nuclear envelope repair and homeostasis. Here, using super resolution structured illumination microscopy, we find that neither CHMP4B nor CHMP2B are increased in ALS neuronal nuclei. In contrast, VPS4 expression is significantly increased in ALS neuronal nuclei prior to the emergence of nuclear pore injury in a CHMP7 dependent manner. However, unlike our prior CHMP7 knockdown studies, impaired VPS4 function does not mitigate alterations to the NPC and the integral transmembrane nucleoporin POM121. Collectively our data suggest that while alterations in VPS4 subcellular localization appear to be coincident with nuclear pore complex injury, therapeutic efforts to mitigate this pathogenic cascade should be targeted towards upstream events such as the nuclear accumulation of CHMP7 as we have previously described. The online version contains supplementary material available at 10.1186/s40478-021-01228-0.
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影响因子：
2.9
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通讯作者：
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