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

大脑在额颞叶变性（FTLD-TDP）和肌萎缩侧索硬化症（ALS）中存在交互反应dna结合蛋白43 （TDP-43）的神经病理学标志磷酸化沉积。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）临床综合征的严重认知障碍有关。据报道，在30-70%的AD病例中，大脑中TDP-43病理与AD的神经病理改变（ADNC）并存，主要影响主要的近期亚型边缘和相关区域，这种模式称为边缘年龄相关的TDP-43脑病神经病理改变（LATE-NC）。研究表明，在没有ADNC的个体中也发现了LATE- nc，假设一种新的tdp -43蛋白病变被称为LATE。LATE是TDP-43蛋白病变中最常见的亚群之一，在30-50%的85岁以上死亡人群中观察到。在比较晚期nc与FTLD-TDP病例时，最近的研究表明，除了不同的临床表现外，流行病学、遗传学和神经影像学特征也存在差异。从神经病理学的角度来看，LATE-NC和FTLD-TDP个体具有TDP-43的一些病理特征。由于磷酸化的TDP-43被确定为FTLD-TDP中泛素阳性内含物的主要成分，因此TDP-43聚集体的五种不同的FTLD-TDP组织病理分布和形态学特征（基于特征A到E建立了临床症状、FTLD-TDP遗传形式和TDP-43神经病理亚型之间的类型）。在FTLD-TDP大脑中的关联已被广泛报道。有趣的是，尽管一些晚期nc病例的TDP-43病理类似于FTLD-TDP A型，但老年人TDP-43蛋白病变的独特神经病理特征是杏仁核中TDP-43免疫反应性的“α”型（类似于A型）或“β”型（与tau缠结结构共混）。TDP-43蛋白病变异质性的分子机制尚不清楚。这种异质性支持“菌株假说”，即具有不同构象的独特致病性TDP-43物种（又称菌株）可能在这种多样性中发挥作用。我们的目标是分离FTLD-TDP和LATE-NC大脑中存在的致病性TDP-43物种，并表征它们在体外和体内的生化特性和生物活性（目的1）。然后，我们将产生体外脑源性TDP-43菌株，再现其人类对应物的特征（目标2）。最后，我们将通过不同TDP-43蛋白病理间的空间谱转录组分析和表达比较，确定脑内是否存在与TDP-43病理神经病理变化相关的不同病理生理信号通路（目的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 ).