Development of mouse models of optineurin-linked ALS

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种麻痹性且通常致命的疾病，由脑和脊髓中的运动神经元变性引起，最终导致呼吸衰竭和死亡。 据估计，ALS影响全球35万人，其中50%在发病后3年内死亡。大多数ALS病例是病因不明的散发性（SALS）。大约5%-10%的ALS病例有家族史（FALS）。视神经磷酸酶（OPTN）的突变已被证明通过未知的机制在不同人群中引起ALS。我们最近的研究表明，OPTN是一个共同的组成部分，在ALS特征的绞样夹杂物在脊髓运动神经元的所有ALS的情况下，除了那些与SOD 1突变。我们的数据，以及以前对TDP 43和FUS的研究提供了重要的证据，支持以下假设：（I）大多数ALS，包括散发性ALS和SOD 1阴性的ALS（约占所有ALS病例的97%），可能在疾病发病机制中共享一些共同元素，尽管病因有很大的多样性，但（II）SOD 1相关的ALS的发病机制（约占所有ALS病例的3%）可能在很大程度上不同于其余ALS。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，但未能显示出有希望的结果。一些化合物对SOD 1G 93 A ALS小鼠模型（用于ALS研究和药物测试的最广泛使用的ALS小鼠模型）显示出治疗效果，但随后在临床试验中对ALS患者没有治疗效果，这可能是由于 OPTN、FUS和TDP 43病理学研究表明，SOD 1相关ALS与其他形式ALS之间的致病途径存在差异。 对这种毁灭性疾病的合理和有效的治疗方法的发展在很大程度上受到对其致病机制的有限认识的阻碍。OPTN相关ALS的发病机制在很大程度上是未知的，其与其他形式的ALS的关系仍有待阐明。我们的初步体外数据表明，OPTN和UBQLN 2在自噬和UPS中具有会聚作用，OPTN和UBQLN 2突变对自噬和UPS的损伤可能有助于ALS中的运动神经元变性。OPTN相关ALS小鼠模型应该成为进一步研究体内致病机制的有价值的工具。在本申请中，我们提出开发三种小鼠模型：OPTNWT转基因、OPTNE 478 G转基因和optn敲除（optn-/-）小鼠模型。一旦建立，我们将存款这些小鼠至杰克逊实验室。 这个项目的成功完成将极有可能提供有价值的工具 对于研究界来说，不仅要研究OPTN连锁的ALS，而且要研究由不同遗传缺陷引起的散发性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）突变已被证明会导致ALS，但疾病机制仍有待阐明。在本申请中，我们建议开发和表征新型OPTN连锁ALS小鼠模型，并将这些小鼠模型提供给研究界。该项目的成功完成将为研究界提供有价值的工具，不仅可以研究OPTN相关的ALS，还可以研究由不同遗传缺陷引起的散发性ALS和家族性ALS的致病机制。 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.