S-Nitrosylation-Dependent Pathological Spread of Abnormal Proteins in Frontotemporal Dementia and Lewy Body Dementia

错误折叠蛋白质的聚集和细胞间扩散是多种神经退行性疾病的标志。 疾病，导致细胞功能障碍、突触损伤和神经元损失。TDP的细胞间增殖- 43，α-突触核蛋白（α-syn）和tau聚集体被认为有助于阿尔茨海默病的疾病进展 阿尔茨海默病（AD）、路易体痴呆（LBD）、额颞叶痴呆（FTD）和其他神经退行性痴呆（CNS）。 疾病此外，越来越多的证据表明，这些蛋白质病往往同时存在于同一组织中。 不同程度的患者。因此，了解这些病理性蛋白质如何在整个组织中传播， 神经系统将为这些疾病的诊断和更有效的治疗开辟新的途径。 在痴呆患者中，突触丢失和神经元损伤部分是由于过度产生的神经元损伤。 活性氧和氮物种（ROS/RNS），由聚集的蛋白质触发。事实上，我们的团队 广泛表明，错误折叠的蛋白质诱导的RNS，如一氧化氮（NO），有助于突触 LBD、AD和FTD模型中通过异常蛋白S-亚硝基化（形成SNO蛋白）造成的损伤。 有趣的是，我们最近发现TDP-43和p62的S-亚硝基化促进了细胞间的 TDP-43和α-syn。我们发现人类的SDP-43和p62都是高度S-亚硝基化的 在患有痴呆症的患者大脑中，以及在hiPSC（人诱导多能干细胞）和患有痴呆症的小鼠模型中， FTD和LBD与对照相比。关于SNO-TDP-43，我们发现S-亚硝基化有助于 TDP-43通过氧化介导的二硫键聚集;这一过程有助于改变RNA- 在TDP-43蛋白质病的基于细胞的和转基因小鼠模型中的结合活性和神经毒性。 此外，我们发现由RNS介导的氧化引发的聚集的TDP-43蛋白的扩散增强， 如FTD所示。关于SNO-p62，我们发现衔接蛋白p62的S-亚硝基化抑制了 自噬通量，导致细胞内积聚和随后的分泌错误折叠的α-syn通过两个直接 细胞外囊泡的释放和分泌。在当前的应用中，我们证明了氧化还原依赖性 异常聚集蛋白在hiPSC模型（2D培养物和3D脑类器官）中的扩散， FTD和LBD小鼠模型。我们使用这些模型来显示（i）用S-亚硝基化/氧化的TDP-43接种 促进TDP-43扩散和TDP-43蛋白质病，（ii）SNO-p62形成促进α-syn扩散， 神经毒性，和（iii）异常的SNO-p62和SNO-TDP-43途径相互作用，以增强TDP-43和α-syn 蔓延

Aggregation and cell-to-cell spread of misfolded proteins are hallmarks of a variety of neurodegenerative diseases, leading to cellular dysfunction, synaptic damage, and neuronal loss. Cell-to-cell propagation of TDP- 43, α-synuclein (α-syn), and tau aggregates is thought to contribute to disease progression in Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and other neurodegenerative diseases. Moreover, mounting evidence suggests that these proteinopathies often co-exist in the same patients to various degrees. Hence, understanding how these pathological proteins spread throughout the nervous system will open up new avenues for diagnostics and more effective therapeutics for these disorders. In patients with dementia, synaptic loss and neuronal damage result in part from excessive generation of reactive oxygen and nitrogen species (ROS/RNS) that is triggered by aggregated proteins. In fact, our group has extensively shown that misfolded protein-induced RNS, such as nitric oxide (NO), contribute to synaptic damage in models of LBD, AD and FTD via aberrant protein S-nitrosylation (forming SNO-proteins). Intriguingly, we recently discovered that S-nitrosylation of TDP-43 and p62 promotes cell-to-cell transmission of TDP-43 and α-syn, respectively. We have found that both TDP-43 and p62 are highly S-nitrosylated in human patient brains with dementia, as well as in hiPSC (human induced pluripotent stem cell) and mouse models of FTD and LBD compared to controls. Concerning SNO-TDP-43, we found that S-nitrosylation contributes to aggregation of TDP-43 via oxidation-mediated disulfide-linkage; this process contributes to altered RNA- binding activity and neurotoxicity in both cell-based and transgenic mouse models of TDP-43 proteinopathy. Moreover, we found enhanced spreading of aggregated TDP-43 protein triggered by RNS-mediated oxidation, as seen in FTD. Concerning SNO-p62, we found that S-nitrosylation of the adaptor protein p62 inhibits autophagic flux, leading to intracellular build-up and consequent secretion of misfolded α-syn via both direct release and secretion of extracellular vesicles. In the current application, we demonstrate redox-dependent spreading of abnormally aggregated proteins in hiPSC models (2D cultures and 3D brain organoids) and mouse models of FTD and LBD. We use these models to show (i) seeding with S-nitrosylated/oxidized TDP-43 promotes TDP-43 spreading and TDP-43 proteinopathy, (ii) SNO-p62 formation promotes α-syn spreading and neurotoxicity, and (iii) aberrant SNO-p62 and SNO-TDP-43 pathways interact to enhance TDP-43 and α-syn spreading.