Mechanisms of Tauopathies and Synucleopathies

描述（由申请人提供）：新出现的证据表明tau蛋白病和突触核蛋白病的病理特征存在相当大的重叠。过度磷酸化的tau，阿尔茨海默病[PD]和其他tau病变的神经元缠结的毒性前体，也发现于某些突触核蛋白病中，而相反，α-突触核蛋白[a-Syn]，一种与帕金森病相关的突触前蛋白，不仅发现于突触核蛋白病中，而且发现于tau病变中。我们已经表明，帕金森病诱导神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶[MPTP]诱导Tau [p-Tau]的过度磷酸化，在存在与PD相关的蛋白质a-Syn的情况下，在多个位点磷酸化。MPTP在p-tau形成中对a-Syn的要求是强制性的，因为在a-Syn缺失小鼠和不表达a-Syn的转染细胞中，MPTP不能诱导p-Tau。我们的数据还表明，p-GSK-Sp，一种与AD和高磷酸化相关的蛋白质，被MPTP激活。重要的是，我们有来自PD和PD+痴呆患者纹状体的人死后组织的数据，这反映了我们在体外和体内模型中观察到的MPTP蛋白水平的变化。这些组合数据表明tau蛋白病和突触核蛋白病的会聚病理机制。在本研究中，我们将使用A53 T转基因小鼠和a-Syn过表达小鼠以及人死后组织，研究MPTP和a-Syn在MPTP帕金森病小鼠模型中诱导p-Tau形成的机制。我们将确定a-Syn及其A30 P/A53 T突变体的聚集体是否改变蛋白质降解途径并具有不同的p-Tau形成动力学。我们将评估已知使Tau过度磷酸化的各种激酶的潜在机制，包括蛋白激酶A、p-ERK和p-GSK-3（3.特别是，使用特异性激酶抑制剂，我们将逆转小鼠中MPTP介导的变性，作为治疗突触核病的新方法。由于与野生型a-Syn相比，α-突触核蛋白的A53 T具有更大的聚集倾向，我们将阐明在过表达突变体的人形式的转基因小鼠中激活p-Tau形成的机制。将在PD和PD伴痴呆患者的人类死后组织中进行平行研究，以衡量我们发现的临床相关性。通过这些研究，将有可能了解Tau蛋白病和突触核蛋白病的重叠病理学和机制，并开发常见的靶向治疗。

DESCRIPTION (provided by applicant): Emerging evidence indicate considerable overlap in the pathological features of tauopathies and synucleopathies. Hyperphosphorylated tau, a toxic precursor of neurofibrillary tangles of Alzheimer's disease [PD] and other taupathies, is also found in certain synucleopathies, while conversely, a-synuclein [a-Syn], a presynaptic protein linked to Parkinson's disease, is found not only in synucleopathies but also in taupathies. We have shown that the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP], induces hyperphosphorylation of Tau [p-Tau], with phosphorylation at multiple sites, in the presence of a-Syn, a protein linked to PD. The requirement for a-Syn in p-tau formation by MPTP was mandatory, since in a-Syn null mice and in transfected cells not expressing a-Syn, MPTP failed to induce p-Tau. Our data also shows that p-GSK-Sp, a protein linked to AD and hyperphasphorylation is activated by MPTP. Importantly, we have data in human post mortem tissue from striata of PD and PD+dementia patients, which mirror changes in protein levels we have observed in the MPTP in vitro and in vivo models. These combined data suggest a convergent pathomechanism for taupathies and synucleopathies. In this grant, we will examine the mechanisms by which MPTP and a-Syn induce p-Tau formation in the MPTP mouse model of parkinsonism, using A53T transgenic mice and a-syn overexpressor mice, and human post mortem tissues. We will determine whether aggregates of a-Syn and its A30P/A53T mutant alter protein degradative pathways and have different kinectics of p-Tau formation. We will assess the underlying mechanisms of various kinases known to hyperphosphorylate Tau, including protein kinase A, p- ERK and p-GSK-3(3. In particular, using specific inhibitors of kinases, we will reverse the MPTP-mediated degeneration in mice, as a novel method to treat synucleopathies. Since the A53T of a-synuclein has a greater propensity to aggregate compared to wild-type a-Syn, we will elucidate the mechanisms of activation of p-Tau formation in the transgenic mouse overexpressing the human form of the mutant. Parallel studies will be conducted in human post mortem tissues of PD and PD with dementia patients, to measure the clinical relevance of our findings. From such studies, it will be possible to understand the overlapping pathology and mechanisms of tauopathies and synucleopathies, and to develop common targeted therapies.