核进口受体 Kapβ2 修饰 C9orf72 相关 ALS/FTD 中聚（GR）介导的神经毒性。
The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD.
机构信息
Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
出版信息
Commun Biol. 2024 Mar 28;7(1):376. doi: 10.1038/s42003-024-06071-2.
Expanded intronic GC repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.
C9ORF72 基因中扩展的内含子 GC 重复序列导致肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）。这些内含子重复通过非 AUG 依赖性机制翻译成五种不同的二肽重复蛋白（DPRs），包括聚甘氨酸-精氨酸（GR），它易于聚集并具有神经毒性。在这里，我们报告 Kapβ2 和 GR 在体外培养的神经元和体内中枢神经系统组织中相互作用，共同聚集。重要的是，这种相互作用显著降低了培养的 GR 表达神经元的死亡风险。Kapβ2 的下调对它们的存活有害，而增加 Kapβ2 水平则减轻了 GR 介导的神经毒性。正如预期的那样，表达 GR 的神经元显示出 TDP-43 核丢失。提高 Kapβ2 水平不会将 TDP-43 恢复到核内，也不会改变 GR 聚集体的动态特性。总的来说，我们的发现支持设计旨在上调 Kapβ2 表达水平的治疗策略，作为对抗 C9orf72-ALS/FTD 神经退行性变的新途径。
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