Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
Institute of Neuroradiology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
Neurobiol Dis. 2019 Dec;132:104559. doi: 10.1016/j.nbd.2019.104559. Epub 2019 Jul 31.
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in the ATXN2 gene, 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 an Atxn2-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 as N-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 on Nat8l mRNA 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.
脊髓小脑性共济失调 2 型（SCA2）是一种常染色体显性遗传性神经退行性疾病，由 ATXN2 基因中的 CAG 扩展突变引起，主要影响脊髓中的运动神经元和小脑中的浦肯野神经元。虽然大的扩展被证明会导致 SCA2，但中等长度的扩展会导致几种萎缩过程的风险增加，包括肌萎缩侧索硬化症和帕金森变体，例如进行性核上性麻痹。为 SCA2 开拓神经保护治疗的努力需要对患者进行纵向监测并确定关键的分子途径。ataxin-2（ATXN2）蛋白主要参与 RNA 翻译控制和应激期间营养代谢的调节。ATXN2 的优先 mRNA 靶标尚未确定。为了了解不同预后阶段的分子疾病机制，我们生成了一种具有完整小鼠 ATXN2 表达调控的 SCA2 中的 Atxn2-CAG100 敲入（KIN）小鼠模型。其特征显示出扩展的体细胞嵌合性，寿命缩短，具有随后表型的进行性时空病理模式，以及脑代谢物如 N-乙酰天冬氨酸（NAA）的异常，所有这些都忠实地反映了 SCA2 患者的发现。在运动缺陷发作之前的阶段进行的新分子分析显示，ATXN2 对编码负责 NAA 合成的酶 Nat8l mRNA 具有强烈的选择性作用。这种代谢物是大脑的主要能量储存物，也是神经元健康的既定标志物。总的来说，我们提出了一种新型的 SCA2 真实啮齿动物模型，其中可行的体内磁共振成像是监测进展的，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 相关疾病的发病机制的关键见解，而且还将有助于开发针对基因的治疗方法和疾病预防。
