Development of mouse models of optineurin-linked ALS

描述(申请人提供)：肌萎缩侧索硬化症(ALS)是一种瘫痪的疾病，通常是致命的，由大脑和脊髓中的运动神经元退化引起，最终导致呼吸衰竭和死亡。据估计，全世界有35万人患有肌萎缩侧索硬化症，其中50%的人在发病后3年内死亡。大多数肌萎缩侧索硬化症病例为散发性(SAL)，病因不明。大约5%-10%的ALS病例有家族病史(FALS)。视神经磷酸酶(optineurin，OPTN)的突变已被证明通过一种未知的机制在不同人群中导致ALS。我们最近发现，OPTN是除SOD1突变外的所有ALS患者脊髓运动神经元中具有ALS特征的Skein样包涵体的常见成分。我们的数据，以及以前对TDP43和FUS的研究提供了重要的证据，支持这样的假设：(I)大多数ALS，包括散发性ALS和SOD1阴性的FAL(约占所有ALS病例的97%)，可能在疾病发病机制上有一些共同的因素，尽管病因有很大的多样性，(Ii)SOD1相关的ALS(约占所有ALS病例的3%)的发病机制可能在很大程度上与其他ALS不同。目前，还没有有效的治疗ALS的方法。已经进行了大量的临床试验，但未能显示出令人振奋的结果。一些化合物在SOD1G93A ALS小鼠模型(ALS研究和药物测试中使用最广泛的ALS小鼠模型)上显示出治疗作用，但在临床试验中对ALS患者没有随后的治疗作用，可能是由于 OPTN、FUS和TDP43的病理研究表明，SOD1连锁的ALS与其他类型的ALS的致病途径存在差异。由于对其致病机制的了解有限，这种毁灭性疾病的合理有效治疗方法的开发在很大程度上受到了阻碍。OPTN连锁肌萎缩侧索硬化症的发病机制尚不清楚，其与其他形式的肌萎缩侧索硬化症的关系仍有待阐明。我们的初步体外数据表明，OPTN和UBQLN2在自噬和UPS中具有趋同作用，OPTN和UBQLN2突变对自噬和UPS的损害可能是ALS运动神经元变性的原因之一。OPTN连锁ALS小鼠模型为进一步研究其体内致病机制提供了有价值的工具。在本申请中，我们建议建立三种小鼠模型：OPTNWT转基因小鼠模型、OPTNE478G转基因小鼠模型和OPTN基因敲除(OPTN-/-)小鼠模型。一旦这些小鼠建立起来，我们就会把它们存入杰克逊实验室。该项目的成功完成将极有可能提供有价值的工具 以便研究界不仅研究OPTN连锁的ALS，而且研究由不同基因缺陷引起的散发性ALS和家族性ALS的致病机制的趋同。此外，这些小鼠模型也可用于筛选和测试潜在的治疗方法。 公共卫生相关性：视神经磷酸酶(OPTN)突变已被证明可导致ALS，但其发病机制仍有待阐明。在本申请中，我们建议开发和表征新的OPTN连锁ALS小鼠模型，并将这些小鼠模型提供给研究社区。该项目的成功完成将为研究界提供有价值的工具，不仅研究OPTN连锁的ALS，而且研究由不同基因缺陷引起的散发性ALS和家族性ALS的致病机制的趋同。此外，这些小鼠模型也可用于筛选和测试潜在的治疗方法。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by degeneration of motor neurons in the brain and spinal cord, eventually leading to respiratory failure and death. ALS affects an estimated 350,000 individuals worldwide, with 50% dying within 3 years of onset. Most ALS cases are sporadic (SALS) of unknown etiology. About 5-10% of ALS cases have a family history (FALS). Mutations in optineurin (OPTN) have been shown to cause ALS in different populations through an unknown mechanism. We have recently shown that OPTN is a common component in the ALS-characteristic skein-like inclusions in the spinal motor neurons of all ALS cases, except for those with SOD1 mutations. Our data, together with those from previous studies of TDP43 and FUS provide important evidence supporting the hypothesis that: (I) most of ALS, including sporadic ALS and SOD1-negative FALS (accounting for approximately 97% of all ALS cases), may share some common elements in the disease pathogenesis, although there is great diversity in the cause~ and (II) the pathogenesis of SOD1-linked ALS (accounting for approximately 3% of all ALS cases) may be largely distinct from the rest of ALS. Currently, there is no effective treatment for ALS. A large number of clinical trials have been carried out, but have failed to show promising results. Some compounds showed therapeutic effect on the SOD1G93A ALS mouse model (the most widely use ALS mouse model for ALS research and drug testing), but not subsequently on ALS patients in clinical trials, possibly due to the difference of pathogenic pathways between SOD1-linked ALS and the rest forms of ALS, as suggested by OPTN, FUS and TDP43 pathological studies. Development of rational and effective therapies for this devastating disease is largely hindered by limited knowledg about its pathogenic mechanism. Pathogenesis of OPTN-linked ALS is largely unknown and its relation to other forms of ALS remains to be elucidated. Our preliminary in vitro data suggest that OPTN and UBQLN2 have a convergent role in autophagy and UPS, and impairment of autophagy and UPS by OPTN and UBQLN2 mutations may contribute to motor neuron degeneration in ALS. OPTN-linked ALS mouse models should be valuable tools for further investigation of the in vivo pathogenic mechanisms. In this application, we propose to develop three mouse models: OPTNWT transgenic, OPTNE478G transgenic and optn knockout (optn-/-) mouse models. We will deposit these mice to the Jackson Laboratories as soon as they are established. Successful completion of this project will be highly likely to provide valuable tools for the research community to study not only the OPTN-linked ALS, but also the convergence of pathogenic mechanisms of sporadic ALS and familial ALS caused by different genetic defects. Moreover, these mouse models may also be used for screening and testing potential therapeutic approaches. PUBLIC HEALTH RELEVANCE: Mutations in optineurin (OPTN) have been shown to cause ALS, but the disease mechanism remains to be elucidated. In this application, we propose to develop and characterize novel OPTN-linked ALS mouse models and make these mouse models available to the research community. Successful completion of this project will provide valuable tools for the research community to study not only the OPTN-linked ALS, but also the convergence of pathogenic mechanisms of sporadic ALS and familial ALS caused by different genetic defects. Moreover, these mouse models may also be used for screening and testing potential therapeutic approaches.