Biochemical and molecular heterogeneity of human TDP-43 proteinopathies in age-related dementias

在额颞叶变性(FTLD-TDP)和肌萎缩侧索硬化症(ALS)中，大脑中存在神经病理标志反式反应DNA结合蛋白43(TDP-43)的磷酸化沉积。此外，在回顾性研究中，TDP-43蛋白病变被证明与模拟阿尔茨海默病(AD)临床综合征的实质性认知障碍有关。据报道，30-70%的AD患者脑内存在TDP-43病理与AD神经病理改变(ADNC)，主要累及近缘及相关区域，这种模式称为边缘年龄相关TDP-43脑病神经病变(Late-NC)。研究表明，在没有ADNC的个体中也发现了晚期NC，这可能是一种新的被指定为晚期的TDP-43蛋白病。晚期是TDP-43蛋白病变最常见的亚型之一，在85岁以上死亡的人中可观察到约30%-50%的人死亡。在比较晚期NC和FTLD-TDP病例时，最近的研究表明，除了不同的临床表现外，它们在流行病学、遗传学和神经影像特征上也有差异。从神经病理学的角度来看，晚期NC和FTLD-TDP患者具有TDP-43的一些病理特征。由于磷酸化的TDP-43被确定为FTLD-TDP泛素阳性包涵体的主要成分，因此建立了5种不同的FTLD-TDP聚集体的组织病理学分布和形态特征(基于特征A到E的临床症状类型、FTLD-TDP的遗传形式和TDP-43神经病理亚型)。FTLD-TDP大脑中的这种联系已经有了广泛的报道。有趣的是，尽管一些晚期NC患者的TDP-43病理类似于FTLD-TDP A型，但与老年人TDP-43蛋白病相关的一个独特的神经病理特征是杏仁核中TDP-43免疫反应的“Alpha”型(类似于A型)或“Beta”型(与tau缠结结构共同混合)。TDP-43蛋白病变异质性背后的分子机制(S)仍不清楚。这种异质性支持一种“品系假说”，即独特的致病TDP-43种(又名。具有不同构象的菌株)可能在这种多样性中发挥作用。我们的目标是分离FTLD-TDP和晚期NC脑中存在的致病TDP-43物种，并在体外和体内鉴定它们的生化特性和生物学活性(目标1)。然后，我们将在体外产生脑源性TDP-43菌株，这些菌株概括了它们的人类同行的特征(目标2)。最后，我们将通过进行不同TDP-43蛋白病变之间的空间分布分析和比较表达来确定是否存在与TDP-43病理的脑内神经病理变化相关的不同的病理生理信号通路(目标3)。

The brain is presence of phosphorylated deposits of the neuropathological hallmark of transactive response DNA-binding protein 43 (TDP-43) in the frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Moreover, in retrospective studies, TDP-43 proteinopathy was shown to be associated with substantial cognitive impairment that mimicked the Alzheimer's disease (AD) clinical syndrome. The co- existence of TDP-43 pathology in brains with neuropathological change of AD (ADNC) has been reported in 30-70% of AD cases, predominantly affecting predominant Recent subtype limbic and associated areas in a pattern called limbic- age-related TDP-43 encephalopathy neuropathological change (LATE-NC). studies have shown that LATE-NC is also found in individuals without ADNC, postulating a new ofTDP-43 proteinopathy designated as LATE. LATE is one of the most prevalent subsets of TDP-43 proteinopathies observed in ~30-50% of people who die beyond 85 years of age. When comparing LATE-NC with FTLD-TDP cases, recent studies have shown that besides distinct clinical manifestations, there are also differences in epidemiological, genetic, and neuroimaging features. From a neuropathological standpoint, LATE-NC and FTLD-TDP individuals share some features of TDP-43 pathology. Since phosphorylated TDP-43 was identified as the major component of ubiquitin-positive inclusions in FTLD-TDP, five distinct FTLD-TDP histopathological distribution and morphological features of TDP-43 aggregates (type between clinical symptoms, genetic forms of FTLD-TDP, and TDP-43 neuropathological subtypes have been established based on characteristic A to E) features . The association in FTLD-TDP brains have been extensively reported. Interestingly, although TDP-43 pathology in some LATE-NC cases resembles FTLD-TDP type A, a distinctive neuropathological feature related to TDP-43 proteinopathy in elderly individuals is type “Alpha” (similar to type A) or type “Beta” (co-mingling with tau tangle structures) pattern of TDP-43 immunoreactivity in the amygdala. The molecular mechanism(s) underlying the heterogeneity of the TDP-43 proteinopathies is still unknown. Such heterogeneity supports a “strain hypothesis” wherein unique pathogenic TDP-43 species (a.k.a. strains) with different conformations may play a role in such diversity. Our objective is to isolate pathogenic TDP-43 species present in FTLD-TDP and LATE-NC brains and characterize their biochemical properties and biological activities in vitro and in vivo (Aim 1). We will then generate in vitro brain-derived TDP-43 strains that recapitulate the characteristic features of their human counterparts (Aim 2). Finally, we will determine whether there are differential pathophysiological signaling pathways associated with neuropathological changes of TDP-43 pathology in the brain by performing spatial profiles between distinct TDP-43 proteinopathies transcriptomic analysis and comparing the expression (Aim 3 ).