Atxn2-CAG100-Knock-In Model for Spinocerebellar Ataxia Type 2

Atxn2-CAG100-2 型脊髓小脑共济失调敲入模型

• 批准号: 100820481
• 负责人: Professor Dr. Georg Auburger
• 金额: --
• 依托单位: Klinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/100820481?language=en
• 关键词: Atxn2; CAG100; Knock; Model; Spinocerebellar

Among the neurodegenerative disorders caused by poly-glutamine domain expansions, Spinocerebellar Ataxia type 2 (SCA2), Amyotrophic Lateral Sclerosis (ALS13) and LevoDopa-responsive Parkinson were reported to be triggered by mutant Ataxin-2, a RNA-binding protein. To model these diseases in mouse, after the published characterization of a 42-glutamine-ATXN2-knock-in we now successfully generated a 100-glutamine-ATXN2-knock-in. Here, we propose to use the cerebellar and brainstem / spinal cord tissue from aged mice to elucidate the progressive neurodegeneration through molecular studies, interaction analyses, calcium-imaging, electrophysiology, histology and behaviour tests. We also plan to establish organotypic cultures of cerebellum to dissect the role of crucial molecules and attempt rescue experiments. Overall, this approach will document tissue-specific effects of expanded ATXN2 on RNAs and proteins, thus identifying molecular and functional biomarkers of pathology.

据报道，在多聚谷氨酰胺结构域扩展引起的神经退行性疾病中，2 型脊髓小脑共济失调 (SCA2)、肌萎缩侧索硬化症 (ALS13) 和左旋多巴反应性帕金森病是由 RNA 结合蛋白 Ataxin-2 突变体引发的。为了在小鼠中模拟这些疾病，在发表 42-谷氨酰胺-ATXN2-敲入的表征后，我们现在成功地生成了 100-谷氨酰胺-ATXN2-敲入。在这里，我们建议使用老年小鼠的小脑和脑干/脊髓组织，通过分子研究、相互作用分析、钙成像、电生理学、组织学和行为测试来阐明进行性神经变性。我们还计划建立小脑的器官型培养物，以剖析关键分子的作用并尝试救援实验。总体而言，这种方法将记录扩展的 ATXN2 对 RNA 和蛋白质的组织特异性影响，从而识别病理学的分子和功能生物标志物。

项目成果

Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation

Atxn2-CAG100 敲入小鼠的产生揭示了由于早期 Nat8l 失调导致的 N-乙酰天冬氨酸生产缺陷

• DOI: 10.1016/j.nbd.2019.104559
• 发表时间: 2019
• 期刊: Neurobiology of Disease
• 影响因子: 6.1
• 作者: Sen NE;Canet-Pons J;Halbach MV;Arsovic A;Pilatus U;Chae WH;Kaya ZE;Seidel K;Rollmann E;Mittelbronn M;Meierhofer D;De Zeeuw CI;Bosman LWJ;Gispert S;Auburger G
• 通讯作者: Auburger G

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

• DOI: 10.3390/ijms20235854
• 发表时间: 2019-12-01
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Sen, Nesli-Ece;Arsovic, Aleksandar;Auburger, Georg
• 通讯作者: Auburger, Georg