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）是一种由大脑和脊髓运动神经元退化引起的麻痹性和通常致命的疾病，最终导致呼吸衰竭和死亡。全球估计有35万人患有ALS，其中50%在发病3年内死亡。大多数ALS病例是病因不明的散发性（SALS）。约5-10%的ALS患者有家族史。在不同的人群中，OPTN的突变通过一种未知的机制导致ALS。我们最近的研究表明，除了SOD1突变外，OPTN是所有ALS病例脊髓运动神经元中ALS特征的束状包裹体的共同成分。我们的数据，以及之前对TDP43和FUS的研究提供了重要的证据，支持以下假设：(1)大多数ALS，包括散发性ALS和sod1阴性的FALS（约占所有ALS病例的97%），尽管在病因上存在很大的多样性，但在疾病发病机制上可能具有一些共同的因素；(2)sod1相关的ALS（约占所有ALS病例的3%）的发病机制可能与其他ALS有很大的不同。目前，ALS还没有有效的治疗方法。已经进行了大量的临床试验，但未能显示出令人鼓舞的结果。一些化合物在SOD1G93A ALS小鼠模型（用于ALS研究和药物测试的最广泛的ALS小鼠模型）上显示出治疗效果，但随后在临床试验中对ALS患者没有效果，可能是由于

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.