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

错误折叠的蛋白质的聚集和细胞间扩散是各种神经退行性疾病的特征 疾病，导致细胞功能障碍、突触损伤和神经元丢失。TDP的细胞间繁殖-- 43、α-突触核蛋白(α-SYN)和tau聚集体被认为与阿尔茨海默病的疾病进展有关 疾病(AD)、路易体痴呆(LBD)、额颞叶痴呆(FTD)和其他神经退行性变 疾病。此外，越来越多的证据表明，这些蛋白质病经常在同一个 不同程度的患者。因此，了解这些病理蛋白质是如何传播到整个 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。 在痴呆症患者中，突触丢失和神经元损伤部分是由于过量产生 由聚集的蛋白质触发的活性氧和氮物种(ROS/RNS)。事实上，我们这群人 已广泛显示错误折叠的蛋白质诱导的RN，如一氧化氮(NO)，有助于突触 LBD、AD和FTD模型通过异常蛋白S-亚硝化(形成SNO-蛋白)的损伤。 有趣的是，我们最近发现，TDP-43和p62的S亚硝化促进了肿瘤的细胞间传递。 TdP-43和α-SYN。我们发现TDP-43和P62在人体内都是高度S亚硝化的 痴呆症患者的大脑，以及人类诱导的多能干细胞和小鼠模型 FTD和LBD与对照组比较。关于SnO-TDP-43，我们发现S-亚硝化有助于 TDP-43通过氧化介导的二硫键聚集；这一过程有助于改变RNA- TDP-43蛋白病细胞模型和转基因小鼠模型的结合活性和神经毒性。 此外，我们还发现RNS介导的氧化促进了聚集的TDP-43蛋白的扩散， 如FTD所示。对于SNO-p62，我们发现接头蛋白p62的S亚硝化抑制了 自噬通量导致细胞内积聚并随后通过两者直接分泌错误折叠的α-SYN 细胞外小泡的释放和分泌。在当前的应用中，我们演示了氧化还原依赖 异常聚集的蛋白质在HiPSC模型(2D培养和3D脑器官)和 FTD和LBD小鼠模型。我们使用这些模型来显示：(I)用S--亚硝化/氧化的TDP-43播种 促进Tdp-43扩散和Tdp-43蛋白病变；(Ii)Sno-p62的形成促进α-syn扩散和 神经毒性，以及(Iii)异常的SNO-p62和SNO-TDP-43信号通路相互作用，增强TdP-43和α-SYN 正在扩散。

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.