Pathologically modified TDP-43 in neurodegenerative diseases

病理修饰的 TDP-43 在神经退行性疾病中的应用

• 批准号: 8263381
• 负责人: Tania France Gendron
• 金额: $ 19.38万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263381
• 关键词: Age; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antibodies; Biological; Biological Assay; Biological Markers; Brain; Brain Pathology; C-terminal; Cerebrospinal Fluid; Cleaved cell; Clinical; Clinical Management; Clinical Research; Clinical Trials; Data; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Evaluation; Face; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Future; Gender; Genes; Goals; Heterogeneity; Impaired cognition; Individual; Investigational Therapies; Link; Liquid substance; Longitudinal Studies; Measurement; Measures; Metric; Molecular; Monitor; Monoclonal Antibodies; Motor; Motor Neuron Disease; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Oryctolagus cuniculus; Pathogenesis; Pathology; Patients; Plasma; Pulmonary function tests; Resources; Sampling; Severity of illness; Sex Characteristics; Testing; Therapeutic; Ubiquitin; Variant; age difference; assay development; base; clinical application; clinically significant; cost; disease diagnosis; disease phenotype; drug efficacy; effective therapy; improved; molecular marker; muscle strength; novel; polyclonal antibody; prospective; protein TDP-43; public health relevance; stem; tau Proteins; therapeutic target; tool; treatment response

DESCRIPTION (provided by applicant): TDP-43 is the principal component of ubiquitin-positive inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Mutations in the gene encoding TDP-43 have been identified in ALS and FTLD with or without motor neuron disease, providing a direct link between TDP-43 and neurodegeneration. Of note, TDP-43 pathology is observed to varying degrees in other neurodegenerative disorders. For instance, TDP-43 inclusions are present in up to 56% of Alzheimer's disease (AD) cases. As with ALS and FTLD-U, the cytosolic deposition of TDP-43 in AD is associated with the presence of abnormally phosphorylated TDP-43 (pTDP-43) and C-terminal TDP-43 fragments (cTDP). Compared to AD patients without TDP-43 pathology, those with TDP-43 pathology are cognitively and functionally worse, suggesting that abnormal TDP-43 causes a modified AD phenotype. Therapeutics that target TDP-43 may thus prove beneficial for this subset of AD patients in addition to ALS and FTLD-U patients. As treatments are investigated, it is essential to prepare for diagnostic issues that will arise when compounds are ready for clinical trials. In the evaluation of new treatments for ALS, FTLD-U and AD, it would be advantageous to be able to distinguish between patients with and without TDP-43 pathology. Thus, the development of antemortem assays that recognize TDP-43 proteinopathies is greatly needed. Moreover, the refinement of biomarker assays is a key strategy, not only for aiding with diagnosis of disease, but also for generating more sensitive measures of disease activity and progression. We hypothesize that the presence of TDP-43-positive inclusions in ALS, FTLD-U and AD suggests that TDP-43 levels in cerebrospinal fluid (CSF) and plasma will parallel TDP-43 brain pathology. Moreover, we believe that the sensitivity and utility of TDP-43 as a biomarker may be enhanced by developing enzyme-linked immunosorbent assays (ELISAs) that detect pathological forms of TDP-43, such as pTDP-43 and cTDP. Therefore, we generated polyclonal antibodies towards pTDP-43 and cTDP and propose to produce similar monoclonal antibodies, as these are critical for the development of reproducible assays with future clinical applications. Using our novel antibodies, we aim to develop sensitive ELISAs for the detection of total and pathological TDP-43 which will be used, together with immunohistochemical analysis of brain TDP-43 pathology, to assess whether pathologically modified TDP-43 in CSF and/or plasma is a reliable indicator of brain TDP-43 pathology in ALS, FTLD-U and AD. Importantly, given that longitudinal data is very limited, we will use both plasma and CSF collected longitudinally from ALS patients to examine pathological TDP-43 levels in relation to clinical presentation and rate of disease progression. PUBLIC HEALTH RELEVANCE: The refinement of biomarkers is a key strategy for elucidating the pathogenesis of neurodegenerative diseases and for developing sensitive measures of disease activity and progression. Overall, the goals of this project are to generate sensitive assays to measure pathologically modified TDP-43 in biological fluids and to validate their use as an urgently needed tool for diagnosing and monitoring the progression of TDP-43 proteinopathies, like amyotrophic lateral sclerosis, frontotemporal dementia with ubiquitin-positive inclusions and Alzheimer's disease cases having TDP-43 pathology. Ultimately, such antemortem assays will provide a molecular basis for improving the early diagnosis of TDP-43 proteinopathies, which is important for the correct clinical management of patients, as well as provide a more efficient and objective evaluation of experimental therapies in clinical trials.

描述（由申请人提供）：TDP-43是肌萎缩侧索硬化症（ALS）和泛素阳性包含物额颞叶变性（FTLD-U）中泛素阳性包含物的主要成分。编码 TDP-43 的基因突变已在患有或不患有运动神经元疾病的 ALS 和 FTLD 中被发现，这提供了 TDP-43 与神经退行性疾病之间的直接联系。值得注意的是，在其他神经退行性疾病中也不同程度地观察到 TDP-43 病理学。例如，高达 56% 的阿尔茨海默病 (AD) 病例中存在 TDP-43 内含物。与 ALS 和 FTLD-U 一样，AD 中 TDP-43 的胞质沉积与异常磷酸化的 TDP-43 (pTDP-43) 和 C 端 TDP-43 片段 (cTDP) 的存在有关。与没有 TDP-43 病理的 AD 患者相比，有 TDP-43 病理的 AD 患者的认知和功能较差，这表明 TDP-43 异常会导致 AD 表型改变。因此，除了 ALS 和 FTLD-U 患者之外，针对 TDP-43 的治疗可能对这部分 AD 患者有益。在研究治疗方法时，必须为化合物准备好进行临床试验时出现的诊断问题做好准备。在评估 ALS、FTLD-U 和 AD 的新疗法时，能够区分患有和不患有 TDP-43 病理的患者将是有利的。因此，非常需要开发识别 TDP-43 蛋白病的死前检测方法。此外，生物标志物检测的改进是一项关键策略，不仅可以帮助诊断疾病，还可以生成更灵敏的疾病活动和进展测量指标。我们假设 ALS、FTLD-U 和 AD 中 TDP-43 阳性包涵体的存在表明脑脊液 (CSF) 和血浆中的 TDP-43 水平与 TDP-43 脑病理学平行。此外，我们相信，通过开发检测 TDP-43 病理形式（例如 pTDP-43 和 cTDP）的酶联免疫吸附测定（ELISA），可以增强 TDP-43 作为生物标志物的敏感性和实用性。因此，我们产生了针对 pTDP-43 和 cTDP 的多克隆抗体，并建议生产类似的单克隆抗体，因为这些对于开发未来临床应用的可重复测定至关重要。利用我们的新型抗体，我们的目标是开发灵敏的 ELISA 来检测总 TDP-43 和病理性 TDP-43，将其与脑 TDP-43 病理学的免疫组织化学分析一起使用，以评估 CSF 和/或血浆中病理修饰的 TDP-43 是否是 ALS、FTLD-U 和 AD 中脑 TDP-43 病理学的可靠指标。重要的是，鉴于纵向数据非常有限，我们将使用从 ALS 患者纵向收集的血浆和脑脊液来检查与临床表现和疾病进展速度相关的病理 TDP-43 水平。 公共卫生相关性：生物标志物的完善是阐明神经退行性疾病发病机制和开发疾病活动和进展的敏感指标的关键策略。总体而言，该项目的目标是生成灵敏的检测方法来测量生物体液中经过病理修饰的 TDP-43，并验证其作为急需的工具的用途，用于诊断和监测 TDP-43 蛋白病的进展，例如肌萎缩侧索硬化症、泛素阳性包含物的额颞叶痴呆和阿尔茨海默病病例 TDP-43 病理学。最终，此类生前检测将为改善 TDP-43 蛋白病的早期诊断提供分子基础，这对于患者的正确临床管理非常重要，并为临床试验中的实验疗法提供更有效和客观的评估。