Developing Diagnostic Nanobodies Against Aggregated TDP-43 Species

描述（由申请人提供）：蛋白质错误折叠和聚集是许多神经退行性疾病背后的共同线索，包括阿尔茨海默病（AD）、路易体痴呆（LBD）和帕金森病（PD）等。虽然每种疾病主要与特定蛋白质的聚集有关; β-淀粉样蛋白（abeta）与AD，tau与AD和其他tau蛋白病，α-突触核蛋白（n-syn）与PD和LBD，一种以上的蛋白质可能在脑组织中错误折叠和聚集，使诊断和治疗策略复杂化。另一种神经元蛋白TDP-43的聚集与肌萎缩侧索硬化症（ALS）和额颞痴呆（FTD）密切相关，并且还与创伤性脑损伤和AD以及其他神经退行性疾病相关。由于由一种蛋白质如abeta的错误折叠和聚集诱导的细胞应激很可能导致其他蛋白质如<$-syn、tau和TDP-43的错误折叠和聚集，因此应预期在不同疾病中存在多种错误折叠蛋白质。因此，表征哪种聚集蛋白种类与每种疾病的不同阶段相关将极大地促进更好的诊断和治疗策略的开发。我们已经产生了几种充分表征的试剂，其特异性地识别Abeta和？-syn的不同聚集种类，并且已经证明所述试剂识别来自患病大脑而不是健康大脑的组织中出现的聚集种类，并且所述试剂也可以具有疾病特异性。在这里，我们将开发和测试类似的试剂，用于检测FTD和ALS脑组织中存在的TDP-43的特定形式。 公共卫生相关性：蛋白质错误折叠和聚集成有毒物质是几种神经退行性疾病背后的常见机制，包括阿尔茨海默氏症、帕金森氏症、额颞痴呆症和肌萎缩侧索硬化症。然而，在这些破坏性疾病的进展过程中，蛋白质聚集如何、何时或何处发生尚不清楚。该项目的重点是开发和使用试剂来检测和定位蛋白质TDP-43的不同错误折叠形式，该蛋白质TDP-43与几种不同的神经退行性疾病有关。该项目直接应用于几种神经退行性疾病以及创伤性脑损伤患者。

DESCRIPTION (provided by applicant): Protein misfolding and aggregation is a common thread behind many neurodegenerative diseases including Alzheimer's disease (AD), Lewy Body Dementia (LBD), and Parkinson's disease (PD) among others. While each disease has been primarily associated with aggregation of a specific protein; beta-amyloid (abeta) with AD, tau with AD and other tauopathies, alpha-synuclein (¿-syn) with PD and LBD, more than one protein is likely to misfold and aggregate in brain tissue complicating diagnosis and treatment strategies. Aggregation of another neuronal protein, TDP-43, has been strongly correlated with amyotrophic lateral sclerosis (ALS) and Frontal Temporal Dementia (FTD) and has also been associated with traumatic brain injury and AD among other neurodegenerative disorders. Since cellular stress induced by misfolding and aggregation of one protein such as abeta may well lead to misfolding and aggregation of other proteins such as ¿-syn, tau and TDP-43, the presence of multiple misfolded proteins in different diseases should be expected. Therefore characterizing which aggregated protein species are correlated with different stages of each disease would greatly facilitate development of better diagnostic and treatment strategies. We have generated several well characterized reagents that specifically recognize different aggregated species of abeta and ¿-syn, and have demonstrated that the reagents recognize aggregated species occurring in tissue from diseased brains, but not healthy brains, and that the reagents can have disease specificity as well. Here we will develop and test similar reagents for detecting specific forms of TDP-43 that are present in FTD and ALS brain tissue. PUBLIC HEALTH RELEVANCE: Protein misfolding and aggregation into toxic species are common mechanisms behind several neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal Temporal Dementia and Amyotrophic lateral sclerosis. However it is not known how, when or where protein aggregation occurs during the progression of these devastating diseases. This project focuses on developing and using reagents to detect and localize different misfolded forms of the protein TDP-43 which has been implicated in several different neurodegenerative diseases. The project has direct applications to several neurodegenerative diseases as well as traumatic brain injury patients.