Disease Mechanisms in Human Ubiquilinopathy

人类泛素病的疾病机制

• 批准号: 8276931
• 负责人: TEEPU SIDDIQUE
• 金额: $ 50.24万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8276931
• 关键词: Accounting; Adult; Affect; Age; Age of Onset; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Autophagocytosis; Behavioral; Brain; Case Study; Cessation of life; Clinical; Cognitive; Communities; Data; Defect; Degradation Pathway; Dementia; Development; Disease; Dominant Genetic Conditions; Economics; Employee Strikes; Etiology; Exhibits; Familial Amyotrophic Lateral Sclerosis; Familial Dementias; Family; Frontotemporal Dementia; Functional disorder; Future; Gender; Genes; Genetic; Genetic Predisposition to Disease; Goals; Hippocampus (Brain); Human; Impairment; In Vitro; Incidence; Individual; Inherited; Knock-out; Knockout Mice; Lewy Body Disease; Life; Link; Lobe; Long-Term Potentiation; Molecular; Motor Cortex; Motor Neurons; Multiple Sclerosis; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Paralysed; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Productivity; Property; Proteins; Quality Control; Reagent; Research; Respiratory Failure; Retirement; Role; Screening procedure; Skeletal Muscle; Spinal Cord; Symptoms; Syndrome; System; Testing; Transgenic Mice; Ubiquitin; cost; driving force; frontal lobe; in vivo; insight; loss of function; mouse model; multicatalytic endopeptidase complex; mutant; mutant mouse model; novel; protein TDP-43; protein degradation; synaptogenesis; ubiquilin; wasting

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of large motor neurons in the brain and spinal cord, resulting in progressive wasting and paralysis of voluntary muscles, respiratory failure and ultimately death. Familial ALS (FALS) accounts for around 10% of all ALS cases, with the majority (90%) of the disease presenting as sporadic ALS (SALS). Discovery of genetic etiologies of ALS has been the driving force in ALS research for the last 20 years. These discoveries have provided fresh insight into pathogenesis and animal models. However, in spite of this effort, global treatments have not been possible for ALS because a common molecular mechanism downstream from the distinct etiologies has not become apparent. It is clear that discovery of additional etiologies and common downstream mechanisms will greatly advance the goals for a molecular understanding of ALS and in finding appropriate treatments. In this application we propose an advance in direction of those goals. We have discovered mutations in UBQLN2 as cause of X-linked dominant ALS and ALS/dementia of the FTD type. The pathology is novel, distinct and unique with ubiquilin2 positive inclusions in the spinal cord and cortex in ALS patients and additional inclusions in the hippocampus of patients with ALS/FTD. To our surprise we found similar ubiquilin2 positive inclusions in all cases of SALS and ALS/FTD and FALS cases studied thus far. None of those cases had mutations in UBQLN2, arguing for a posttranslational role for ubiquilin2 in ALS as a whole. Our initial in vitro and in vivo data suggest a dysfunction of the ubiquilin proteasome syndrome (UPS) and autophagy in the presence of mutant ubiquilin2. In addition, cognitive and behavioral deficits and decreased long term potentiation in far field recordings were observed in transgenic mice expressing a pathogenic UBQLN2 mutation (P497H). In this project, we propose four specific aims to understand the disease causing mechanism(s) of mutant ubiquilin2. We will establish pathological, cognitive and other behavioral phenotypes and their electrophysiological correlates in our current and to be developed mouse models of mutant ubiquiln2. We will also use our already established ubqln2 knockout mouse model and develop ubqln1 knockout and double knockouts of ubqln1/ubqln2 to test if mutant ubiquilin2 defects are manifestation of a loss of function of ubiquilin2 in relationto the UPS and autophagy systems or whether mutant ubiquilin2 exhibits a novel toxic property. Successful completion of this project will not only provide insight into understanding the pathogenic mechanism of X-linked ALS, but also rapidly provide the wider research community with useful reagents for future studies and for screening and testing potential therapies. The outcome of this project will also have important implications in the understanding of the pathogenesis and treatment of other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting an estimated 350,000 individuals worldwide, with 50% dying within 3 years of onset. The cost to the family approaches $200,000 per year in the final years of illness and the disease defies all treatment. Discovery of diverse genetic causes of ALS has been the driving force in ALS research for the last 20 years by providing fresh insight into mechanisms of disease. It is clear that discovery of additional causes of ALS and unifying mechanisms of disease will greatly advance the goals for a molecular understanding of ALS and in finding appropriate treatments. We have discovered mutations in a gene called UBQLN2 as a cause of a form of inherited ALS and ALS/dementia and an exciting and unique pathology in sporadic and familial ALS as well as ALS/dementia. Functional studies have revealed an impairment of protein degradation pathways in the presence of mutant form of ubiquilin2. Though impaired protein degradation is thought to be associated with the formation of detrimental protein inclusions in the development of many neurodegenerative disorders, direct evidence of mutations in this pathway is limited. Hence, ubiquilin2, by virtue of a common pathology across ALS and ALS/dementia presents a unique opportunity to study the effect of its mutations on cellular protein quality control with a view to understand the pathogenic mechanism by which the UBQLN2 mutations cause neurodegeneration. We will develop and analyze appropriate animal models in this study to identify molecular mechanisms by which mutant ubiquilin2 causes imbalance in the protein economy of neurons which result in impaired synapse formation and leads to clinical syndromes of ALS and dementia.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）的特征在于脑和脊髓中大运动神经元的变性，导致随意肌的进行性消耗和麻痹、呼吸衰竭并最终死亡。家族性ALS（Fals）约占所有ALS病例的10%，其中大多数（90%）疾病表现为散发性ALS（SALS）。在过去的20年里，ALS遗传病因的发现一直是ALS研究的驱动力。这些发现为发病机制和动物模型提供了新的见解。然而，尽管做出了这些努力，但ALS的全球治疗尚不可能，因为不同病因下游的共同分子机制尚未变得明显。很明显，发现其他病因和共同的下游机制将大大推进ALS的分子理解和寻找适当的治疗方法的目标。在本申请中，我们提出了这些目标的方向的进步。我们已经发现UBQLN 2突变是X连锁显性ALS和FTD型ALS/痴呆的原因。病理学是新颖、独特和独特的，ALS患者的脊髓和皮质中存在泛素2阳性包涵体，ALS/FTD患者的海马中存在额外的包涵体。令我们惊讶的是，我们在迄今为止研究的所有SALS和ALS/FTD和FALS病例中发现了相似的泛素2阳性包涵体。这些病例都没有UBQLN 2突变，这表明泛蛋白2在ALS中的翻译后作用是整体性的。我们最初的体外和体内数据表明，泛素蛋白酶体综合征（UPS）和自噬功能障碍的突变体泛素2的存在下。此外，在表达致病性UBQLN 2突变（P497 H）的转基因小鼠中观察到认知和行为缺陷以及远场记录中的长时程增强降低。在这个项目中，我们提出了四个具体的目标来了解突变体ubiquilin 2的致病机制。我们将建立病理，认知和其他行为表型和他们的电生理相关在我们目前和将要开发的突变体ubiquiln 2小鼠模型。我们还将使用我们已经建立的ubqln 2敲除小鼠模型，并开发ubqln 1敲除和ubqln 1/ubqln 2的双敲除，以测试突变体ubiquilin 2缺陷是否是ubiquilin 2与UPS和自噬系统相关的功能丧失的表现，或者突变体ubiquilin 2是否表现出新的毒性。该项目的成功完成不仅将为理解X连锁ALS的致病机制提供深入的见解，而且还将为更广泛的研究界提供有用的试剂，用于未来的研究以及筛选和测试潜在的治疗方法。该项目的结果也将对理解其他神经退行性疾病的发病机制和治疗产生重要影响。 公共卫生相关性：肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，全球约有35万人患病，其中50%在发病后3年内死亡。在患病的最后几年，家庭每年的费用接近20万美元，这种疾病无法治疗。在过去的20年里，ALS的多种遗传原因的发现一直是ALS研究的驱动力，为疾病机制提供了新的见解。很明显，发现ALS的其他原因和统一的疾病机制将大大推进ALS的分子理解和寻找适当的治疗方法的目标。我们发现了一种名为UBQLN 2的基因突变，它是一种遗传性ALS和ALS/痴呆的原因，也是散发性和家族性ALS以及ALS/痴呆中令人兴奋和独特的病理学。功能研究已经揭示了在存在突变形式的泛素2的情况下蛋白质降解途径的损害。虽然受损的蛋白质降解被认为与许多神经退行性疾病发展中有害蛋白质内含物的形成有关，但该途径突变的直接证据有限。因此，由于ALS和ALS/痴呆的共同病理学，泛素2提供了研究其突变对细胞蛋白质质量控制的影响的独特机会，以了解UBQLN 2突变引起神经变性的致病机制。在本研究中，我们将开发和分析适当的动物模型，以确定突变型泛素2导致神经元蛋白质经济失衡的分子机制，从而导致突触形成受损，并导致ALS和痴呆的临床综合征。