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

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）和帕金森病的tau病变的重要病理标志。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。帕金森氏E3泛素连接酶功能的丧失与早发性帕金森氏症有关。淀粉样蛋白的积累，包括PD中的a-突触核蛋白和AD中的¿-淀粉样蛋白，是各自疾病进展的起始步骤。几种蛋白质，包括a-突触核蛋白，是已知的白金泛素连接酶活性的靶标。初步数据首次表明，野生型帕金蛋白降低了细胞内A¿42的稳态水平，这表明细胞内淀粉样蛋白可能也是帕金蛋白泛素连接酶活性的靶点。A -和A -突触核蛋白沉积物在某些重叠的神经退行性疾病中与tau共存，如痴呆和帕金森病，然而，尚不清楚它们如何与tau相互作用，从而在tau病变中引起神经原纤维缠结的形成。初步数据显示，野生型帕金可减弱人神经母细胞瘤SH-SY5Y细胞中tau与a-突触核蛋白或¿-淀粉样蛋白联合的毒性，但不能显著降低单独的tau毒性。因此，帕金可以降低细胞内a-突触核蛋白和-淀粉样蛋白水平，从而在细胞培养和动物模型中阻止它们形成触发tau修饰的“淀粉样模板”。

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.