Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation
Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation
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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
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发表时间：
2019
影响因子：
6.1
通讯作者：
Auburger G
中科院分区：
文献类型：
--
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
脊髓小脑性共济失调2型（SCA2）是一种常染色体显性神经退行性疾病，主要影响脊髓运动神经元和小脑浦肯野神经元。虽然大的扩张被证明会导致SCA2，但中等长度的扩张会导致几种萎缩过程的风险增加，包括肌萎缩性侧索硬化症和帕金森变体，例如进行性核上性麻痹。要大力开拓SCA2的神经保护疗法，需要对患者进行纵向监测，并确定关键的分子通路。ataxin-2 （ATXN2）蛋白主要参与应激期的RNA翻译、控制和营养代谢调控。ATXN2的优先mRNA靶点尚未确定。为了了解不同预后阶段的分子疾病机制，我们建立了具有完整小鼠ATXN2表达调控的SCA2小鼠ATXN2 - cag100敲入（KIN）模型。其特征揭示了SCA2患者的躯体嵌合性扩张，寿命缩短，病理的进行性时空模式与随后的表型，以及脑代谢物如n -乙酰天冬氨酸（NAA）的异常，所有这些都反映了SCA2患者的发现。新的分子分析显示，在运动缺陷发生之前，ATXN2对编码NAA合成酶的nat8lmrna具有很强的选择性作用。这种代谢物是大脑中重要的能量储存物，也是神经元健康的公认标志。总的来说，我们提出了一种新的真实的SCA2啮齿动物模型，其中体内磁共振成像可以监测进展，并且可以定义最早的转录异常。我们相信该模型不仅将揭示SCA2和其他atxn2相关疾病的病理机制，而且还将有助于开发基因靶向治疗和疾病预防。
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in theATXN2gene, mainly affecting motor neurons in the spinal cord and Purkinje neurons in the cerebellum. While the large expansions were shown to cause SCA2, the intermediate length expansions lead to increased risk for several atrophic processes including amyotrophic lateral sclerosis and Parkinson variants, e.g. progressive supranuclear palsy. Intense efforts to pioneer a neuroprotective therapy for SCA2 require longitudinal monitoring of patients and identification of crucial molecular pathways. The ataxin-2 (ATXN2) protein is mainly involved in RNA translation control and regulation of nutrient metabolism during stress periods. The preferential mRNA targets of ATXN2 are yet to be determined. In order to understand the molecular disease mechanism throughout different prognostic stages, we generated anAtxn2-CAG100-knock-in (KIN) mouse model of SCA2 with intact murine ATXN2 expression regulation. Its characterization revealed somatic mosaicism of the expansion, with shortened lifespan, a progressive spatio-temporal pattern of pathology with subsequent phenotypes, and anomalies of brain metabolites such asN-acetylaspartate (NAA), all of which mirror faithfully the findings in SCA2 patients. Novel molecular analyses from stages before the onset of motor deficits revealed a strong selective effect of ATXN2 onNat8lmRNA which encodes the enzyme responsible for NAA synthesis. This metabolite is a prominent energy store of the brain and a well-established marker for neuronal health. Overall, we present a novel authentic rodent model of SCA2, where in vivo magnetic resonance imaging was feasible to monitor progression and where the definition of earliest transcriptional abnormalities was possible. We believe that this model will not only reveal crucial insights regarding the pathomechanism of SCA2 and other ATXN2-associated disorders, but will also aid in developing gene-targeted therapies and disease prevention.
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DOI：
10.1007/s12031-012-9949-4
发表时间：
2013-09
期刊：
Journal of molecular neuroscience : MN
影响因子：
--
作者：
Drost J;Nonis D;Eich F;Leske O;Damrath E;Brunt ER;Lastres-Becker I;Heumann R;Nowock J;Auburger G
通讯作者：
Auburger G
基于解剖学的中枢体感系统系统研究指南及其在 2 型脊髓小脑共济失调 (SCA2) 患者中的应用
影响因子：
5
作者：
U. Rüb;C. Schultz;K. Tredici;K. Gierga;G. Reifenberger;R. D. Vos;C. Seifried;H. Braak;G. Auburger
通讯作者：
G. Auburger
影响因子：
4.5
作者：
Al-Ramahi I;Pérez AM;Lim J;Zhang M;Sorensen R;de Haro M;Branco J;Pulst SM;Zoghbi HY;Botas J
通讯作者：
Botas J
意大利南部脊髓小脑共济失调 2 型人群的生存预测因素
影响因子：
3.3
作者：
A. Antenora;D. Bruzzese;M. Lieto;A. Roca;Maria Teresa Florio;S. Peluso;F. Saccà;G. De Michele;F. Santorelli;A. Filla
通讯作者：
A. Filla
影响因子：
3.5
作者：
Di Fabio, Roberto;Santorelli, Filippo;Casali, Carlo
通讯作者：
Casali, Carlo