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: 7794950
• 负责人: Charbel Moussa
• 金额: $ 12.24万
• 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/7794950
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Animal Model; Attenuated; Award; Brain; Brain Chemistry; Cell Culture Techniques; Cells; Cellular Stress; Cessation of life; Citric Acid Cycle; Data; Dementia; Deposition; Disease Progression; Epitopes; Gene Transfer; Human; In Vitro; Lesion; Magnetic Resonance Imaging; 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; alpha synuclein; 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; 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）：蛋白质聚集是帕金森病[PD]、阿尔茨海默病[AD]和帕金森病tau蛋白病的重要病理标志。 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。 Parkin 的 E3 泛素连接酶功能丧失与早发性帕金森病有关。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。已知包括α-突触核蛋白在内的多种蛋白质是parkin泛素连接酶活性的靶标。初步数据首次表明，野生型parkin降低了细胞内A¿42的稳态水平，提高了细胞内Ν-淀粉样蛋白也是parkin泛素连接酶活性的靶标的可能性。在某些重叠的神经退行性疾病（如痴呆和帕金森病）中，A¿ 和 α-突触核蛋白沉积物均与 tau 共存，然而，尚不清楚它们中的任何一个如何与 tau 相互作用以引发跨 tau 病的神经原纤维缠结形成。初步数据表明，野生型parkin可减弱tau蛋白与α-突触核蛋白或β-淀粉样蛋白结合对人神经母细胞瘤SH-SY5Y细胞的毒性，但不能显着降低单独的tau蛋白毒性。因此，parkin 可能会降低细胞内 α-突触核蛋白和 β-淀粉样蛋白的水平，从而阻止它们形成“淀粉样蛋白模板”，从而在细胞培养物和体内动物模型中触发 tau 修饰。 Parkin 将细胞从细胞内 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出来，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。这项研究预计将表明 Parkin 能够恢复淀粉样蛋白诱导的线粒体 ATP 能量不足，从而影响蛋白酶体活性，从而防止蛋白质的毒性积累。我将建立基因转移动物模型，以研究 Parkin 在降低淀粉样蛋白“模板”水平方面的作用，抵消其对线粒体的毒性作用以及 tau 细胞病和帕金森病综合征中 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，其中parkin作为E3泛素连接酶以减少细胞内蛋白质积累，线粒体保护剂能够恢复ATP能量水平，治疗痴呆和帕金森症等神经退行性疾病。