Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis

在该研究中，许教授课题组鉴定了一个在Tau疾病中起关键致病作用的新蛋白Appoptosin。Tau疾病是一类具有共同病理特征：即随着疾病的进程，在脑中会产生Tau蛋白异常聚集和缠结的神经退行性疾病，包括阿尔茨海默症（老年性痴呆）、额颞痴呆、以及进行性核上麻痹（PSP）等。虽然人们推测Tau蛋白异常很可能是导致这些疾病中神经元和脑功能受损的关键因素，但是并不清楚它究竟是如何诱发疾病的。尤其是PSP患者在平衡、眼球运动以及思维上都存在严重的障碍，但迄今为止，人们对该疾病的致病机制几乎一无所知。许教授的研究团队通过对PSP患者的检测，发现一个与该疾病相关的DNA单核苷酸突变（SNP）可以引起Appoptosin蛋白水平的增高，并增加Tau蛋白的过度磷酸化以及caspase-3酶介导的Tau蛋白切割，从而导致Tau蛋白的异常聚集和突触功能障碍。更为重要的是，在阿尔茨海默症和额颞痴呆患者的脑组织中，同样发现了致病蛋白Appoptosin和Tau蛋白异常切割的增加，进一步证明了Appoptosin介导的途径在Tau疾病的发病机制中起到了关键性作用。该研究为进一步阐明神经退行性疾病的病理机制指引了新的研究方向，为痴呆和运动功能障碍的临床治疗提供了全新的治疗靶点和思路，具有重要的临床意义。Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer’s disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects

Binding of TDP-43 to the 3′UTR of Its Cognate mRNA Enhances Its Solubility

TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of a broad range of neurodegenerative diseases termed TDP-43 proteinopathies, which encompass a spectrum of diseases ranging from amyotrophic lateral sclerosis to frontotemporal dementia. Pathologically misfolded and aggregated forms of TDP-43 are found in cytoplasmic inclusion bodies of affected neurons in these diseases. The mechanism by which TDP-43 misfolding causes disease is not well-understood. Current hypotheses postulate that the TDP-43 aggregation process plays a major role in pathogenesis. We amplify that hypothesis and suggest that binding of cognate ligands to TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation. We expressed recombinant TDP-43 containing an N-terminal Venus yellow fluorescent protein tag in <i>Escherichia coli</i> and induced its aggregation by altering solvent salt concentrations and examined the extent to which various oligonucleotide molecules affect its aggregation <i>in vitro</i> using aggregation-induced turbidity assays. We show that vYFP-TDP-43 binding to its naturally occurring RNA target that comprises a sequence on the 3′UTR region of its mRNA improves its solubility, suggesting interplay among TDP-43 solubility, oligonucleotide binding, and TDP-43 autoregulation