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）和额颞叶变性伴泛素阳性包涵体（FTLD-U）中泛素阳性包涵体的主要成分。编码TDP-43的基因突变已在伴或不伴运动神经元疾病的ALS和FTLD中被鉴定，这提供了TDP-43和神经变性之间的直接联系。值得注意的是，在其他神经退行性疾病中观察到不同程度的TDP-43病理学。例如，TDP-43内含物存在于高达56%的阿尔茨海默病（AD）病例中。与ALS和FTLD-U一样，AD中TDP-43的胞质沉积与异常磷酸化TDP-43（pTDP-43）和C-末端TDP-43片段（cTDP）的存在相关。与没有TDP-43病理的AD患者相比，具有TDP-43病理的AD患者在认知和功能上更差，这表明异常TDP-43引起修饰的AD表型。因此，靶向TDP-43的治疗剂可能证明除了ALS和FTLD-U患者之外，还对该AD患者亚组有益。在研究治疗方法时，必须为化合物准备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的新治疗方法时，能够区分具有和不具有TDP-43病理的患者将是有利的。因此，非常需要开发识别TDP-43蛋白病的死前测定。此外，生物标志物测定的改进是一个关键策略，不仅用于辅助疾病诊断，而且用于产生疾病活动和进展的更灵敏的测量。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水平将与TDP-43脑病理学平行。此外，我们认为，TDP-43作为生物标志物的灵敏度和实用性可以通过开发检测TDP-43的病理形式（如pTDP-43和cTDP）的酶联免疫吸附测定（ELISA）来增强。因此，我们产生了针对pTDP-43和cTDP的多克隆抗体，并提出产生类似的单克隆抗体，因为这些对于开发具有未来临床应用的可重复测定法至关重要。使用我们的新型抗体，我们的目标是开发用于检测总TDP-43和病理TDP-43的灵敏ELISA，其将与脑TDP-43病理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CSF来检查与临床表现和疾病进展速率相关的病理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的发病机制和开发疾病活动和进展的敏感措施的关键策略。总的来说，该项目的目标是产生灵敏的测定来测量生物液体中病理修饰的TDP-43，并验证它们作为诊断和监测TDP-43蛋白病进展的迫切需要的工具的用途，如肌萎缩性侧索硬化症，具有泛素阳性包涵体的额颞叶痴呆症和具有TDP-43病理的阿尔茨海默病病例。最终，这种死前检测将为改善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价。