Neurodegenerative diseases are characterized by progressive cognitive decline and the loss of neurons in the central nervous system; many are also characterized by abnormal aggregation of misfolded proteins. Ubiquitin (Ub) is a eukaryotic protein that plays pivotal roles in protein degradation and cellular signaling. Ubiquitinated aggregates are observed in neurodegenerative diseases; this ultimately results in reduced levels of available or free Ub. However, it remains unclear whether neurotoxicity arises from the aggregates or a deficiency of free Ub. To investigate this, we treated primary neurons of mouse embryonic brains with amyloid beta (Aβ) 42 and found that free Ub levels were decreased and cell viability was reduced in Aβ42-treated neurons. As reduced levels of free Ub are closely related to impaired function of the proteasome, we evaluated proteasome activity and found that proteasome activity was reduced upon treatment of primary neurons and mouse brain slices with Aβ42. Therefore, we conclude that proteotoxic stress from Aβ42 treatment reduced the levels of available Ub and decreased proteasome activity, resulting in inflammatory stress and apoptosis of neurons.

中文翻译：

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淀粉样β聚集体处理的培养神经元和脑组织中游离泛素水平和蛋白酶体活性降低。

神经退行性疾病的特征是进行性认知功能减退和中枢神经系统神经元的丧失。许多还以错误折叠的蛋白质的异常聚集为特征。泛素（Ubiquitin，Ub）是一种真核蛋白质，在蛋白质降解和细胞信号传导中起着关键作用。在神经退行性疾病中观察到泛素化的聚集体。最终导致可用或免费Ub的数量减少。但是，尚不清楚神经毒性是否是由聚集体或游离Ub缺乏引起的。为了对此进行研究，我们用淀粉样蛋白β（Aβ）42处理了小鼠胚胎大脑的原代神经元，发现在用Aβ42处理的神经元中，游离Ub含量降低，细胞活力降低。由于游离Ub的减少与蛋白酶体功能受损密切相关，我们评估了蛋白酶体的活性，发现用Aβ42处理原代神经元和小鼠脑片后，蛋白酶体的活性降低。因此，我们得出结论，来自Aβ42处理的蛋白毒性应激降低了可用Ub的水平并降低了蛋白酶体的活性，从而导致了炎症应激和神经元的凋亡。