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: 8093934
• 负责人: Tania France Gendron
• 金额: $ 23.25万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093934
• 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; 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(申请人提供)：TDP-43是肌萎缩侧索硬化症(ALS)和额颞叶变性泛素阳性包涵体(FTLD-U)泛素阳性包涵体的主要成分。编码TDP-43的基因突变已经在ALS和FTLD中被发现，无论是否有运动神经元疾病，提供了TDP-43和神经退行性变之间的直接联系。值得注意的是，TDP-43病理在其他神经退行性疾病中也有不同程度的观察。例如，多达56%的阿尔茨海默病(AD)病例中存在TDP-43包涵体。与ALS和FTLD-U一样，AD患者TDP-43的胞浆沉积与异常磷酸化的TDP-43(pTDP-43)和C末端TDP-43片段(CTDP)的存在有关。与无TDP-43病理的AD患者相比，有TDP-43病理的AD患者在认知和功能方面更差，提示TDP-43异常导致AD表型改变。因此，除了ALS和FTLD-U患者外，靶向TDP-43的治疗药物可能对这类AD患者有益。随着治疗方法的研究，为化合物准备进行临床试验时出现的诊断问题做好准备是至关重要的。在评估ALS、FTLD-U和AD的新治疗方法时，能够区分有和没有TDP-43病理的患者将是有利的。因此，开发识别TDP-43蛋白病变的生前检测方法是非常必要的。此外，改进生物标记物分析是一项关键战略，不仅有助于疾病的诊断，而且还有助于产生更灵敏的疾病活动和进展指标。我们推测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TDP-43水平与TDP-43脑病理平行。此外，我们认为，TDP-43作为生物标志物的敏感性和实用性可以通过开发检测TDP-43病理形式的酶联免疫吸附试验(ELISA)来提高，例如pTDP-43和cTDP。因此，我们制备了针对pTDP-43和cTDP的多克隆抗体，并建议生产类似的单抗，因为这些抗体对于开发具有未来临床应用的可重复性的检测方法至关重要。使用我们的新抗体，我们的目标是建立检测总TDP-43和病理TDP-43的灵敏ELISA，并将其与脑TDP-43病理的免疫组织化学分析结合使用，以评估脑脊液和/或血浆中病理修饰的TDP-43是否是ALS、FTLD-U和AD脑TDP-43病理的可靠指标。重要的是，由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病理TDP-43水平与临床表现和疾病进展速度的关系。 公共卫生相关性：生物标记物的改进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指标的关键策略。总体而言，该项目的目标是产生灵敏的分析方法来测量生物液中病理修饰的TDP-43，并验证它们作为诊断和监测TDP-43蛋白病变(如肌萎缩侧索硬化症、泛素阳性包涵体的额颞痴呆和具有TDP-43病理的阿尔茨海默病病例)的迫切需要的工具的使用。最终，这种生前检测将为改进TDP-43蛋白病的早期诊断提供分子基础，这对正确的临床处理非常重要，并在临床试验中提供更有效和客观的实验治疗评估。