A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration
A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration
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DOI：
10.1073/pnas.0812819106
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发表时间：
2009-02-17
影响因子：
11.1
通讯作者：
Kay, Steve A.
中科院分区：
文献类型：
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作者：
Chu, Jessie;Hong, Nancy A.;Kay, Steve A.
通过全基因组N-乙基-N-亚硝基脲（ENU）诱变筛选，鉴定出小鼠神经系统突变体lister。纯合子lister小鼠表现出严重的早发性和进行性神经和运动功能障碍。lister编码环指蛋白LISTERIN，其在体外起E3泛素连接酶的作用。虽然李斯特菌广泛表达于所有组织，运动和感觉神经元和脑干和脊髓中的神经元过程在突变体中主要受到影响。病理学体征包括神经胶质增生、营养不良性神经突、空泡化线粒体和可溶性过度磷酸化tau蛋白的积累。通过靶向基因陷阱插入产生的不同lister等位基因的分析揭示了LISTERIN是胚胎发育所需的，并证实了LISTERIN调节过程的直接干扰导致神经变性。lister小鼠揭示了参与神经退行性疾病的途径，并可能作为理解人类神经退行性疾病的分子机制的模型。
A mouse neurological mutant, lister, was identified through a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Homozygous lister mice exhibit profound early-onset and progressive neurological and motor dysfunction. lister encodes a RING finger protein, LISTERIN, which functions as an E3 ubiquitin ligase in vitro. Although lister is widely expressed in all tissues, motor and sensory neurons and neuronal processes in the brainstem and spinal cord are primarily affected in the mutant. Pathological signs include gliosis, dystrophic neurites, vacuolated mitochondria, and accumulation of soluble hyperphosphorylated tau. Analysis with a different lister allele generated through targeted gene trap insertion reveals LISTERIN is required for embryonic development and confirms that direct perturbation of a LISTERIN-regulated process causes neurodegeneration. The lister mouse uncovers a pathway involved in neurodegeneration and may serves as a model for understanding the molecular mechanisms underlying human neurodegenerative disorders.