Mechanisms of Tauopathies and Synucleopathies

Tau蛋白病和突触核蛋白病的机制

基本信息

批准号：
8522657
负责人：
ANITA SIDHU
金额：
$ 9万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8522657
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-Methyl-4-phenylpyridinium Aftercare Age Alzheimer&apos s Disease Autopsy Biological Models Brain region Cells Chronic Comorbidity Corpus striatum structure Cyclic AMP-Dependent Protein Kinases Cytoskeleton Data Degradation Pathway Dementia Disease Dissociation Dose Free Radicals Frontotemporal Dementia Generations Genes Glycogen Synthase Kinase 3 Grant Human In Vitro Inclusion Bodies Knockout Mice Lead Lewy Bodies Link Measures Mediating Methods Microtubules Modeling Mus Mutation Nerve Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neurotoxins Parkinson Disease Parkinson&apos s Dementia Parkinsonian Disorders Pathology Patients Pattern Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Process Progressive Supranuclear Palsy Proteins Reaction Time Role Series Site Tauopathies Testing Tissues Toxic effect Toxin Transgenic Mice alpha synuclein base clinically relevant cytotoxicity dopamine transporter hyperphosphorylated tau in vivo in vivo Model kinase inhibitor link protein mouse model mutant neuroblastoma cell neurotoxicity novel overexpression presynaptic prevent protein aggregate protein aggregation protein complex sarkosyl synucleinopathy tau Proteins tau mutation uptake

项目摘要

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.

描述（由申请人提供）：新兴证据表明，在青春期和突触核心病的病理特征上有很大的重叠。在某些突触肺炎中也发现了高磷酸化的tau，这是阿尔茨海默氏病神经原纤维缠结[PD]和其他taupathies的毒性前体，而相反，A-Synuclein [A-Syn]（A-Syn），一种与帕金森氏病相关的a核蛋白[A-syn] [A-syn]，也发现了Syncithies insuctaties syncalies。我们已经表明，帕金森氏症诱导神经毒素1-甲基-4-苯基1,2,3,6-四氢吡啶[MPTP]，诱导tau [p-tau]的高磷酸化，在多个位点具有磷酸化，在多个位置，在A-ysyn，蛋白质链接的情况下，蛋白质链接。 MPTP在P-TAU形成中对A-Syn的要求是强制性的，因为在A-Syn Null小鼠和未表达A-Syn的转染细胞中，MPTP未能诱导P-TAU。我们的数据还表明，与AD相关的蛋白质P-GSK-S-SP被MPTP激活。重要的是，我们从PD和PD+痴呆症患者的纹状体中具有人类验尸组织中的数据，这反映了我们在MPTP体外和体内模型中观察到的蛋白质水平的变化。这些组合的数据表明了针曲和突触核疗法的收敛致病力机制。在这笔赠款中，我们将使用A53T转基因小鼠和A-Synn过表达小鼠以及人类的验尸组织，研究MPTP和A-Syn在MPTP小鼠的MPTP小鼠模型中诱导P-TAU形成的机制。我们将确定A-Syn及其A30p/A53T突变体的聚集体是否会改变蛋白质降解途径，并且具有不同的P-TAU形成动力学。我们将评估已知的多磷酸tau的各种激酶的潜在机制，包括蛋白激酶A，P-erk和P-GSK-3（特别是3。，特别是使用激酶的特定抑制剂，我们将逆转MPTP介导的小鼠中的MPTP介导的变性，作为一种较大的方法来治疗A-Sypoliceplacepolage and a-sequect a-sey to a-sey a-Syn and a-sy nos a sy n a sy n a sys and a n and a n and and and and a sys and a sys and and and and and。野生型A-syn，我们将阐明在过表达突变体的人类形式的转基因小鼠中P-TAU形成的机制。突触性疾病，并开发常见的靶向疗法。