Validation of a novel tau clearance mechanism.

除了细胞外β-淀粉样蛋白（Aβ）斑块沉积外，阿尔茨海默病（AD）在病理上是 其特征在于细胞内tau蛋白病， 微管相关蛋白MAPT/tau形成神经元缠结（NFT），导致功能丧失， 神经元虽然Aβ斑块在启动AD发病机制中起关键作用，但认知功能下降的严重程度与AD的发病机制密切相关。 与新皮质NFT的负担最相关。因此，促进累积的tau蛋白的清除， 代表了tau蛋白病患者的一种有前途的治疗策略，这取决于更好地了解 疾病进展期间病理性tau种类降解的潜在机制。我们 最终目标是阐明tau蛋白病（如AD）如何启动和 进展，并开发有效的治疗方法来治疗tau蛋白病。据报道，tau可以被 通过自噬-溶酶体或泛素-蛋白酶体系统降解。Tau的降解与 其各种翻译后修饰，包括磷酸化、乙酰化和泛素化。我们 初步研究表明，在正常小鼠脑组织中，tau蛋白被线性遍在蛋白链修饰， 在tau蛋白病小鼠模型中显著降低。tau蛋白的线性泛素化促进tau蛋白清除 以一种自噬依赖的方式我们进一步发现，氧化应激可以增加去泛素化酶OTULIN， 活性通过促进其磷酸化，这两个都大大增加了脑组织中的AD 患者抑制OTULIN可防止病理性tau蛋白种类的积累，并减弱其表达。 在tau蛋白病小鼠模型中的细胞毒性。因此，我们假设线性泛素化促进tau蛋白 降解，这是抑制去泛素化酶OTULIN;氧化应激激活OTULIN，导致 增加的tau聚集和神经毒性。OTULIN的药理学抑制可减轻tau蛋白病 通过增强tau聚集体的清除来促进进展。提出了三个具体目标来检验这一点 假说. aim 1将决定线性泛素化在调节tau蛋白积累和神经元凋亡中的作用。 毒性并研究自噬-溶酶体机制。Aim 2将研究氧化应激介导的 使用系统生物学方法研究OTULIN诱导的tau蛋白病期间的机制。目标3将测试一个新的 在tau蛋白病动物中开发了促进tau蛋白清除并减轻其细胞毒性的OTULIN抑制剂 模型我们的研究将通过提供以下方面产生重大影响：1）调节tau聚集的新机制 和蛋白毒性; 2）氧化应激和tau线性泛素化之间的新机制联系; 3）潜在的 用于减轻tau蛋白病和认知下降的治疗方法，最终使AD患者受益。

Besides extracellular β-amyloid (Aβ) plaques deposition, Alzheimer’s disease (AD) is pathologically characterized by intracellular tauopathy that accumulation and aggregation of abnormally hyperphosphorylated microtubule-associated protein MAPT/tau form neurofibrillary tangle (NFT), resulting in loss of functional neurons. Although Aβ plaques play a key role in initiating AD pathogenesis, the severity of cognitive decline correlates best with the burden of neocortical NFTs. Therefore, promoting the clearance of accumulated tau represents a promising therapeutic strategy for tauopathy patients, which depends on a better understanding of the mechanisms underlying the degradation of pathological tau species during disease progression. Our ultimate goal is to elucidate the complex mechanisms underlying how tauopathies, such as AD, initiate and progress, and to develop effective therapeutic approaches to treat tauopathies. It is reported that tau can be degraded by autophagy-lysosomal or ubiquitin-proteasomal systems. Tau degradation is closely associated with its various post-translational modifications, including phosphorylation, acetylation, and ubiquitination. Our preliminary studies indicate that tau is modified by linear ubiquitin chains in normal mouse brain tissues, which were substantially decreased in tauopathy mouse models. Linear ubiquitination of tau promotes tau clearance in an autophagy-dependent manner. We further found that oxidative stress can increase deubiquitinase OTULIN activity by promoting its phosphorylation, which both are substantially increased in the brain tissues from AD patients. Inhibition of OTULIN prevented the accumulation of pathological tau species and attenuated its cytotoxicity in a tauopathy mouse model. Therefore, we hypothesize that linear ubiquitination promotes tau degradation, which is inhibited by deubiquitinase OTULIN; oxidative stress activates OTULIN, resulting in increased tau aggregation and neurotoxicity. Pharmacological inhibition of OTULIN may mitigate tauopathy progression by enhancing the clearance of tau aggregates. Three specific aims are proposed to test this hypothesis. Aim1 will determine the role of linear ubiquitination in regulating tau accumulation and neuronal toxicity and investigate the autophagic-lysosomal mechanism. Aim2 will investigate oxidative stress-mediated mechanisms during OTULIN-induced tauopathies using a systems biology approach. Aim 3 will test a newly developed OTULIN inhibitor in promoting tau clearance and mitigating its cellular toxicity in tauopathy animal models. Our studies will have a strong impact by providing: 1) novel mechanisms regulating tau aggregation and proteotoxicity; 2) new mechanistic link between oxidative stress and tau linear ubiquitination; 3) potential therapeutic approaches for mitigating tauopathy and cognitive decline, eventually benefiting AD patients.