Giel Korsten, Miriam Osinga, Robin A Pelle, Albert K Serweta, Baukje Hoogenberg, Harm H Kampinga, Lukas C Kapitein
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引用次数: 0
摘要
亨廷顿氏病(Huntington's disease,HD)是由亨廷丁蛋白的多聚谷氨酰胺扩增导致多聚谷氨酰胺聚集体的形成引起的。导致复杂的 HD 病理的毒性机制仍只有部分了解。在这里,我们展示了核聚谷氨酰胺聚集体会诱发核包膜(NE)出血和破裂,而这种破裂往往不能完全修复。这些破裂与核薄层的破坏同时发生,并导致薄层瘢痕的形成。膨胀显微镜能够解析核聚集体的超微结构,并发现多聚谷氨酰胺纤维粘附在破裂部位的细胞膜上,这表明了一种不完全修复的机制。此外,我们还发现 NE 修复因子经常聚集在核聚集体附近,这与修复停滞一致。这些发现表明,核聚Q聚集体诱导的NE完整性丧失是亨廷顿氏病和其他多聚谷氨酰胺疾病的潜在诱因。
Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair.
Huntington's disease (HD) is caused by a polyglutamine expansion of the huntingtin protein, resulting in the formation of polyglutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington's disease and other polyglutamine diseases.
期刊介绍:
The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.