CAT-tails: A Novel Type of Protein Modification Implicated in Neurodegeneration

我们已经确定了ENU诱导的小鼠核输出中介因子的两个独立突变 (NEMF)导致具有许多肌萎缩侧索硬化症表型特征的运动神经元病 (ALS)。NEMF最近被证明是停滞不前的核糖体质量控制复合体的关键组成部分 (RQC)，允许泛素化、聚合Ala/Thr尾巴(CAT-Tail)的C-末端添加和处置 核糖体停滞的新生多肽链。联合-Pi Joazeiro之前曾描述过一种小鼠模型 另一个RQC复合体成员Listerin(Ltn1)的ENU突变引起的神经退行性变。在几个月内 在某些方面，Ltn1-enu表型与ALS的其他小鼠模型相似，包括新发现的 NEMF小鼠模型，从而巩固了RQC功能障碍和神经退行性变之间的联系。 初步研究发现人类散发性肌萎缩侧索硬化症患者存在罕见的潜在破坏性NEMF 多态现象。因此，新的NEMF小鼠模型的鉴定为 确定蛋白质质量控制机制的缺陷如何导致神经疾病。我们 假设错误的核糖体质量控制可能是运动神经元病的基础，而NEMF是 一个可能的新的肌萎缩侧索硬化症相关疾病基因，对调节正常神经功能至关重要。 好了！

We have identified two independent ENU-induced mouse mutations in the nuclear export mediating factor (Nemf) causing a motor neuron disease with many phenotypic hallmarks of amyotrophic lateral sclerosis (ALS). NEMF has recently been shown to be a key component of the stalled-ribosome quality control complex (RQC) that allows for ubiquitination, C-terminal addition of poly Ala/Thr tails (CAT-tails) and disposal of ribosome-stalled nascent polypeptide chains. Co-PI Joazeiro has previously characterized a mouse model of neurodegeneration caused by ENU mutation of another RQC complex member, Listerin (Ltn1). In several ways, the Ltn1-ENU phenotype resembles that of other mouse models of ALS including the newly discovered Nemf mouse models, thus solidifying the connection between RQC dysfunction and neurodegeneration. Preliminary work has identified human sporadic ALS patients with rare and potentially damaging NEMF polymorphisms. Thus, the identification of the novel NEMF mouse model provides a key resource for determining how defects in protein quality control mechanisms may lead to neurological disease. We hypothesize that misregulated ribosomal quality control can underlie motor neuron disease, and that NEMF is a putative new ALS-associated disease gene critical for regulating normal neuronal function. !