Parkin protection in gene transfer animal models (KO-1 Award)

基因转移动物模型中的 Parkin 保护（KO-1 奖）

• 批准号: 7464171
• 负责人: Charbel Moussa
• 金额: $ 11.3万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464171
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Animal Model; Attenuated; Award; Brain; Brain Chemistry; Cells; Cessation of life; Citric Acid Cycle; Cultured Cells; Data; Dementia; Deposition; Disease Progression; Epitopes; Gene Transfer; Human; In Vitro; Lesion; Localized; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Metabolism; Mitochondria; Modification; Molecular Conformation; NMR Spectroscopy; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Parkinsonian Disorders; Pathology; Phosphoric Monoester Hydrolases; Phosphorous; Phosphorylation; Phosphotransferases; Process; Proteins; Protons; Research; Role; Spectrum Analysis; Stress; Syndrome; Tauopathies; Therapeutic; Time; Tin; Toxic effect; Toxin; Ubiquitination; attenuation; early onset; energy balance; in vivo; multicatalytic endopeptidase complex; neurofibrillary tangle formation; parkin gene/protein; prevent; protein aggregation; protein misfolding; relating to nervous system; synuclein; tau Proteins; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Protein aggregation comprises an important pathological landmark in Parkinson's disease [PD], Alzheimer's disease [AD] and the tauopathies with Parkinsonism. Parkin is an E3 ubiquitin-ligase involved in the proteasomal degradation of misfolded proteins. Loss of parkin's E3 ubiquitin-ligase function is associated with early onset Parkinsonism. Accumulation of amyloid proteins, including a-synuclein in PD and ¿-amyloid in AD, is the initiating step in their respective disease progression. Several proteins, including a-synuclein, are known to be targets of parkin ubiquitin-ligase activity. Preliminary data show for the first time that wild type parkin decreases the steady-state levels of intracellular A¿42, raising the possibility that intracellular ¿-amyloid is also a target for the ubiquitin-ligase activity of parkin. Both A¿ and a-synuclein deposits variably co-exist with tau in certain overlapping neurodegenerative diseases with dementia and Parkinsonism, however, it is not known how either of them interacts with tau to provoke neurofibrillary tangle formation across the tauopathies. Preliminary data show that wild type parkin attenuates tau combined with either a-synuclein or ¿-amyloid toxicity in human neurblastoma SH-SY5Y cells, but fails to significantly decrease tau toxicity alone. Therefore, parkin may reduce intracellular a-synuclein and ¿-amyloid levels, thus preventing them from forming "amyloid templates" that trigger tau modification in cell culture and animal models in vivo. Parkin rescues cells from intracellular A¿42 and a-synuclein toxicity as well as mitochondrial toxins-induced stress, and these effects are concurrent with decreased amyloid levels and increased proteasome activity. This research is expected to show that parkin is capable of restoring amyloid-induced mitochondrial ATP energy deficits, which affect proteasome activity to prevent toxic accumulation of proteins. I will generate gene transfer animal models to investigate the role of parkin to decrease the level of amyloid 'templates', counteracting their toxic effects on the mitochondria and alteration of tau metabolism in the spectrum of syndromes with tau cytopathy and Parkinsonism. These studies may provide a potential double-pronged therapeutic strategy involving parkin as an E3 ubiquitin-ligase to reduce intracellular protein accumulation, and mitochondrial protectant capable of restoring ATP energy levels, in the spectrum of neurodegenerative diseases with dementia and Parkinsonism.

描述（由申请人提供）：蛋白质聚集包括帕金森病[PD]、阿尔茨海默病[AD]和伴有帕金森综合征的tau蛋白病中的重要病理标志。Parkin是一种E3泛素连接酶，参与错误折叠蛋白的蛋白酶体降解。帕金E3泛素连接酶功能的丧失与早发性帕金森综合征相关淀粉样蛋白的积累，包括PD中的α-突触核蛋白和AD中的β-淀粉样蛋白，是其各自疾病进展的起始步骤。已知几种蛋白质，包括α-突触核蛋白，是帕金泛素连接酶活性的靶标。初步数据首次显示，野生型帕金蛋白降低了细胞内A42的稳态水平，提高了细胞内A42-淀粉样蛋白也是帕金蛋白泛素连接酶活性靶点的可能性。两个A？和α-突触核蛋白沉积物在某些重叠的神经变性疾病与痴呆和帕金森综合征中与tau共同存在，然而，尚不清楚它们中的任一种如何与tau相互作用以引起跨tau蛋白病的神经元缠结形成。初步数据显示，野生型帕金减弱tau与α-突触核蛋白或β-淀粉样蛋白在人神经母细胞瘤SH-SY 5 Y细胞中的毒性组合，但不能显著降低单独的tau毒性。因此，帕金可以降低细胞内α-突触核蛋白和β-淀粉样蛋白水平，从而防止它们形成“淀粉样蛋白模板”，在体内细胞培养和动物模型中触发tau修饰。 帕金从细胞内A 42和α-突触核蛋白毒性以及线粒体毒素诱导的应激中拯救细胞，这些作用与淀粉样蛋白水平降低和蛋白酶体活性增加同时发生。这项研究有望表明，帕金能够恢复淀粉样蛋白诱导的线粒体ATP能量不足，这会影响蛋白酶体活性，以防止蛋白质的毒性积累。我将产生基因转移动物模型，以研究帕金降低淀粉样蛋白“模板”水平的作用，抵消它们对线粒体的毒性作用，以及tau细胞病和帕金森综合征综合征中tau代谢的改变。这些研究可能提供一种潜在的双管齐下的治疗策略，涉及帕金作为E3泛素连接酶，以减少细胞内蛋白质的积累，和线粒体保护剂能够恢复ATP能量水平，在神经退行性疾病与痴呆和帕金森氏症的频谱。