Investigating how nuclear pore components exploit an ER-dependent quality control pathway

摘要 肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病， 神经元，导致进行性肌肉无力和瘫痪。没有治愈ALS或 额颞叶痴呆症（FTD），主要是因为目前还不清楚是哪一种 所涉及的细胞途径是致病的。越来越多的研究发现， 核孔复合物（NPC）作为ALS病变组织和 ALS模型。这种损伤的特征是核质转运缺陷， NPC组分（“NUP”）向胞质溶胶的错误定位。 为了研究定位错误的Nups的命运，我们的研究小组开发了一个NPC模型， 破坏，从而我们耗尽一个关键的结构Nup和跟踪其他Nup的本地化。 引人注目的是，我们的初步数据表明，移位的Nups在内质网中形成聚集体， 内质网，这是一个过程，这是依赖于ER跨膜蛋白kinectin。这些 聚集体在主要的自噬因子Beclin-1耗尽后积累，这表明 NUP是ER偶联自噬的靶向。总之，这些发现指出了一种新的核-ER 自噬途径，可能是功能时，NUPS在ALS中被取代。基于此 根据初步数据，我们假设细胞运动蛋白驱动蛋白-1将Nups从 细胞核转运到ER（Aim 1A），并且这种转运过程也发生在疾病相关细胞中 培养模式（Aim 1B）。我们进一步假设，一旦在ER，Nup聚集体被清除 受体介导的自噬（Aim 2）。这项工作将阐明基本的细胞内运输， 质量控制途径。更重要的是，理解细胞对错误定位的核蛋白的反应， 可以提供ALS/FTD进展的更好机制图。

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily targets motor neurons, leading to progressive muscle weakness and paralysis. There is no cure for ALS or the related disorder frontotemporal dementia (FTD), largely because it is unclear which of the many implicated cellular pathways are causative. A growing number of studies have identified damage to the nuclear pore complex (NPC) as a key pathological phenotype in both ALS-diseased tissue and ALS models. This damage is characterized by defective nucleocytoplasmic transport and mislocalization of NPC components (“Nups”) to the cytosol. To examine the fate of mislocalized Nups, our research group has developed a model for NPC disruption whereby we deplete a key structural Nup and track the localization of other Nups. Strikingly, our preliminary data shows that the displaced Nups form aggregates in the endoplasmic reticulum, a process which is dependent on the ER transmembrane protein kinectin. These aggregates accumulate upon depletion of the major autophagy factor Beclin-1, suggesting that the Nups are targeted for ER-coupled autophagy. Together, these findings point to a novel nucleus-to-ER autophagy pathway that may be functioning when Nups are displaced in ALS. Based on this preliminary data, we hypothesize that the cellular motor protein kinesin-1 transports Nups from the nucleus to the ER (Aim 1A), and that this transport process also occurs in a disease-relevant cell culture model (Aim 1B). We further hypothesize that once at the ER, the Nup aggregates are cleared by receptor-mediated autophagy (Aim 2). This work will elucidate basic intracellular trafficking and quality control pathways. More importantly, understanding cellular response to mislocalized Nups may provide a better mechanistic picture of the progression of ALS/FTD.