Intraneuronal inclusions containing ubiquitylated filamentous protein aggregates are a common feature of many of the major human neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Loss of function mutations in enzymes of the ubiquitin conjugation/deconjugation pathway are sufficient to cause familial forms of neurodegenerative diseases, suggesting that failure of ubiquitin-mediated proteolysis could also be central to inclusion formation in the more common sporadic cases. Examination of ubiquitin-positive inclusions at the protein level provides evidence of attempted proteasomal proteolysis, however close inspection of the temporal aspects of inclusion formation indicates that ubiquitylation is probably a late event. In this regard, the presence of ubiquitin within inclusions of idiopathic neurodegenerative disorders may indicate not a primary dysfunction of ubiquitin-mediated proteolysis, but rather a secondary, presumably protective cellular response. Within this model, other factors are likely to be initiating in inclusion biogenesis. Consistent with these proposals, non-ubiquitylated forms of the principal ubiquitylated components of Alzheimer's disease neurofibrillary tangles and Parkinson's disease Lewy bodies, tau and alpha-synuclein proteins, respectively, can be degraded by proteasomes in a pathway which does not have an absolute requirement for ubiquitylation. Inhibition of proteasome function in the pathological state, as has been reported in both Alzheimer's and Parkinson's disease, could therefore contribute both to accumulation of non-ubiquitylated forms of aggregation-prone neuronal proteins, as well as impaired clearance of ubiquitylated aggregates.

中文翻译：

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泛素介导的蛋白水解在神经退行性疾病发病机理中的作用。

包含泛素化丝状蛋白聚集体的神经内包涵体是许多主要的人类神经退行性疾病的常见特征，包括阿尔茨海默氏病和帕金森氏病。泛素结合/去结合途径酶功能突变的丧失足以引起家族形式的神经退行性疾病，这表明在更常见的散发病例中，泛素介导的蛋白水解失败也可能是包涵体形成的关键。在蛋白质水平上对泛素阳性包裹体的检查提供了蛋白酶体蛋白水解尝试的证据，但是仔细检查包裹体形成的时间方面，表明泛素化可能是一个晚期事件。在这方面，特发性神经退行性疾病内含泛素的存在可能不是泛素介导的蛋白水解的主要功能障碍，而是继发性的，可能是保护性的细胞反应。在此模型中，其他因素可能是包涵体生物发生的起始原因。与这些提议一致，蛋白酶体可以通过阿尔茨海默氏病神经原纤维缠结和帕金森氏病路易体，tau和α-突触核蛋白蛋白的主要泛素化成分的非泛素化形式降解，而该途径并不绝对需要泛素化。如在阿尔茨海默氏病和帕金森氏病中所报道的，在病理状态下蛋白酶体功能的抑制，