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

额颞叶痴呆和路易体痴呆中异常蛋白的 S-亚硝基化依赖性病理学扩散

基本信息

批准号：
10291048
负责人：
Tomohiro Nakamura
金额：
$ 208.19万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291048
关键词：
3-Dimensional ALS patients Adaptor Signaling Protein Alzheimer&apos s Disease Amyloid beta-Protein Brain C9ORF72 CRISPR/Cas technology Cells Cerebrum Characteristics Dementia Diagnostic Disease Disease Progression Disulfide Linkage Exocytosis Frontotemporal Dementia Functional disorder GTF2H1 gene Generations Genes Human Injury Journals Knockout Mice Lead Lewy Body Dementia Link Mediating Modeling Monitor Mutation Nature Nervous system structure Neurodegenerative Disorders Neurons Nitric Oxide Nitrogen Organoids Oxidation-Reduction Oxides Oxygen Parkinson Disease Pathologic Pathology Pathway interactions Patients Post-Translational Protein Processing Process Protein S Proteins Publishing RNA Binding Regulation SKIL gene Science Seeds Synapses TDP-43 aggregation Techniques Tissues Transgenic Mice Transgenic Model alpha synuclein base extracellular vesicles frontotemporal lobar dementia-amyotrophic lateral sclerosis in vivo induced pluripotent stem cell misfolded protein mouse model mutant neuron loss neurotoxicity oxidation protein TDP-43 protein aggregation synucleinopathy tau aggregation therapeutically effective transmission process

项目摘要

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.

错误折叠蛋白的聚集和细胞间传播是多种神经退行性的标志疾病，导致细胞功能障碍，突触损伤和神经元丧失。 TDP-的细胞间传播 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氏症的疾病进展疾病（AD），Lewy身体痴呆（LBD），额颞痴呆（FTD）和其他神经退行性疾病。此外，越野证据表明，这些蛋白质病通常在同一中共存患者到各种程度。因此，了解这些病理蛋白如何在整个过程中传播神经系统将为这些疾病开辟新的诊断途径和更有效的治疗方法。在痴呆症患者中，突触损失和神经元损害的一部分是由于过量产生由聚集的蛋白触发的活性氧和氮种（ROS/RN）。实际上，我们的小组已广泛表明，蛋白质诱导的RN（例如一氧化氮（NO））有助于突触 LBD，AD和FTD模型的损害通过异常蛋白S-硝基化（形成SNO蛋白质）的损害。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到细胞的传播 TDP-43和α-Syn。我们发现TDP-43和P62在人类中都是高度S-硝基化的患有痴呆症的患者大脑以及HIPSC（人类诱导的多能干细胞）和小鼠模型与对照组相比，FTD和LBD。关于SNO-TDP-43，我们发现S-硝基化有助于 TDP-43通过氧化介导的二硫键连接聚集；这个过程有助于改变RNA- TDP-43蛋白质病的基于细胞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介导的氧化触发的聚集的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-亚硝基化抑制自噬通量，导致细胞内积累，并通过两种直接折叠的α-Syn分泌细胞外蔬菜的释放和分泌。在当前应用中，我们证明了依赖氧化还原的在HIPSC模型（2D培养物和3D脑器官）中扩散绝对聚集的蛋白质和 FTD和LBD的鼠标模型。我们使用这些模型显示（i）用S-硝基化/氧化的TDP-43播种促进TDP-43扩散和TDP-43蛋白质病，（ii）SNO-P62形成促进α-Syn扩散和神经毒性，以及（iii）异常SNO-P62和SNO-TDP-43途径相互作用以增强TDP-43和α-Syn 蔓延。