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（ALS）中，脑内存在神经病理学标志的反式反应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蛋白质病被证明与模仿阿尔茨海默病（AD）临床综合征的实质性认知障碍相关。在30-70%的AD病例中报告了脑中TDP-43病理与AD的神经病理学变化（ADNC）的共存，主要影响主要的新近亚型边缘和相关区域，其模式称为边缘-年龄相关TDP-43脑病神经病理学变化（LATE-NC）。研究表明LATE-NC也存在于没有ADNC的个体中，假定一种新的TDP-43蛋白质病称为LATE。LATE是TDP-43蛋白病中最常见的子集之一，在85岁以上死亡的人群中观察到约30-50%。当比较LATE-NC与FTLD-TDP病例时，最近的研究表明，除了不同的临床表现外，在流行病学，遗传学和神经影像学特征方面也存在差异。 从神经病理学的角度来看，LATE-NC和FTLD-TDP个体共享TDP-43病理学的一些特征。由于磷酸化TDP-43被鉴定为FTLD-TDP中泛素阳性包涵体的主要成分，因此已基于特征性A至E特征建立了TDP-43聚集体的五种不同FTLD-TDP组织病理学分布和形态学特征（临床症状之间的类型、FTLD-TDP的遗传形式和TDP-43神经病理学亚型）。FTLD-TDP脑中的相关性已被广泛报道。有趣的是，尽管一些LATE-NC病例中的TDP-43病理学类似于FTLD-TDP A型，但老年个体中与TDP-43蛋白质病相关的独特神经病理学特征是杏仁核中TDP-43免疫反应性的“α”型（类似于A型）或“β”型（与tau缠结结构共混合）模式。TDP-43蛋白病异质性的分子机制仍不清楚。这种异质性支持“菌株假说”，其中独特的致病性TDP-43物种（也称为具有不同构象的菌株）可能在这种多样性中起作用。我们的目标是分离存在于FTLD-TDP和LATE-NC脑中的致病性TDP-43物种，并在体外和体内表征其生化特性和生物活性（目的1）。然后，我们将在体外产生脑源性TDP-43菌株，其概括了其人类对应物的特征（目的2）。最后，我们将通过在不同的TDP-43蛋白病转录组学分析之间进行空间分布并比较表达来确定是否存在与脑中TDP-43病理学的神经病理学变化相关的不同病理生理学信号传导途径（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 ).