Developing neuroprotective strategies for proteinopathy

制定蛋白质病的神经保护策略

• 批准号: 8761701
• 负责人: Brian C. Kraemer
• 金额: $ 29.53万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761701
• 关键词: Address; Advanced Development; Amyotrophic Lateral Sclerosis; Automobile Driving; Behavioral; Binding; CDC7 gene; Caenorhabditis elegans; Calcineurin; Cell Culture Techniques; Cessation of life; Complex; Cultured Cells; DNA-Binding Proteins; Dementia; Deposition; Detergents; Development; Disease; Dissection; Exhibits; Familial Amyotrophic Lateral Sclerosis; Figs - dietary; Frontotemporal Lobar Degenerations; Functional disorder; Funding; Future; Genetic; Genomics; Goals; Human; Investigation; Lead; Lesion; Link; Mammals; Masks; Mediating; Modeling; Molecular; Motor; Motor Neurons; Mutation; Nerve Degeneration; Neuronal Dysfunction; Neurons; Pathogenesis; Pathology; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Proteins; Relative (related person); Role; Serine; Staging; Surveys; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transgenic Mice; Ubiquitin; Work; base; calcineurin phosphatase; disability; effective therapy; genome-wide; kinase inhibitor; multicatalytic endopeptidase complex; neuropathology; neurotoxic; neurotoxicity; premature; prevent; protein TDP-43; public health relevance; research study; small molecule; tau Proteins; therapeutic target; ubiquilin

DESCRIPTION (provided by applicant): Developing neuroprotective strategies for proteinopathy. The lesions seen in the degenerating neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) consist primarily of abnormal TDP-43 protein. Pathological TDP-43 containing deposits associated with motor neuron neurodegeneration are the hallmark pathology in over 90% of ALS cases, including both familial and sporadic types. How aggregated, ubiquitinated and phosphorylated TDP-43 protein causes neuronal dysfunction and neurodegeneration remains incompletely understood. This work focuses on extending previous studies to complete the molecular dissection of the mechanisms causing neurodegeneration in ALS and FTLD. In the previous funding period we characterized a C. elegans model of ALS mutation driven TDP-43 proteinopathy and investigated the molecular, cellular, and genomic basis of TDP-43 neurotoxicity. We identified phosphorylation of TDP-43 at serines 409/410 as a critical molecular species driving neurotoxicity, and identified kinases modulating neurodegeneration by controlling the accumulation of phosphorylated TDP-43. The specific aims of this competitive renewal are: 1) Determine the relative toxicity of phosphorylated wild type TDP-43 and the role of kinase activation in the genesis of phosphorylated TDP-43; 2) Identify the cellular machinery responsible for detoxifying phosphorylated TDP-43 3) Dissect the mechanisms by which Ubiquilin mediates TDP-43 neuropathology and neurodegeneration. The development of neuroprotective strategies for TDP-43 related neuropathology in ALS and FTLD is the long term objective of this work. By completing the proposed experiments we will construct additional models of sporadic ALS/FTLD, address the critical question of whether or not pS409/410 TDP-43 is a neurotoxic species in mammals, dissect the molecular mechanism mediating TDP-43 toxicity and capitalize on this information to develop new translationally relevant neuroprotective strategies for targeting TDP-43 neurotoxicity.

描述（由申请人提供）：开发蛋白质疗法的神经保护策略。肌萎缩性侧硬化症（ALS）和额颞Lobar变性（泛素蛋白阳性夹杂物（FTLD-U））在退化的神经元中看到的病变主要由TDP-43蛋白质异常组成。病理TDP-43包含与运动神经元神经变性相关的沉积物是超过90％的ALS病例（包括家族性和零星类型）的标志性病理。综合，泛素化和磷酸化的TDP-43蛋白会导致神经元功能障碍和神经变性尚不完全了解。这项工作着重于扩展以前的研究，以完成导致ALS和FTLD中神经退行性的机制的分子解剖。在上一个资金期间，我们表征了ALS突变驱动的TDP-43蛋白质病的秀丽隐杆线虫模型，并研究了TDP-43神经毒性的分子，细胞和基因组基础。我们将TDP-43在丝氨酸409/410上的磷酸化确定为驱动神经毒性的关键分子物种，并通过控制磷酸化的TDP-43的积累来鉴定激酶调节神经变性。这种竞争性更新的具体目的是：1）确定磷酸化野生型TDP-43的相对毒性，以及激酶激活在磷酸化TDP-43生成中的作用； 2）确定负责排毒磷酸化的TDP-43 3）的细胞机制，剖析泛素介导TDP-43神经病理学和神经变性的机制。 TDP-43与ALS和FTLD相关的神经病理学的神经保护策略的发展是这项工作的长期目标。通过完成提出的实验，我们将构建其他散发性ALS/FTLD的模型，解决一个关键问题，即PS409/410 TDP-43是否是哺乳动物中的神经毒性物种 靶向TDP-43神经毒性的策略。