Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Bioessays. 2022 Jul;44(7):e2100287. doi: 10.1002/bies.202100287. Epub 2022 May 6.
Fibrillar protein aggregates are the pathological hallmark of a group of age-dependent neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Aggregates of the microtubule-associated protein Tau are observed in Alzheimer's disease and primary tauopathies. Tau pathology propagates from cell to cell in a prion-like process that is likely subject to modulation by extracellular chaperones such as Clusterin. We recently reported that Clusterin delayed Tau fibril formation but enhanced the activity of Tau oligomers to seed aggregation of endogenous Tau in a cellular model. In contrast, Clusterin inhibited the propagation of α-Synuclein aggregates associated with Parkinson's disease. These findings raise the possibility of a mechanistic link between Clusterin upregulation observed in Alzheimer's disease and the progression of Tau pathology. Here we review the diverse functions of Clusterin in the pathogenesis of neurodegenerative diseases, focusing on evidence that Clusterin may act either as a suppressor or enhancer of pathology.
纤维状蛋白聚集体是一组与年龄相关的神经退行性疾病的病理学特征，包括阿尔茨海默病和帕金森病。微管相关蛋白 Tau 的聚集体在阿尔茨海默病和原发性 Tau 病中被观察到。Tau 病理学通过类似于朊病毒的过程从一个细胞传播到另一个细胞，这种过程可能受到细胞外伴侣蛋白如 Clusterin 的调节。我们最近报道称，Clusterin 延迟了 Tau 纤维的形成，但增强了 Tau 低聚物的活性，以在细胞模型中引发内源性 Tau 的聚集。相比之下，Clusterin 抑制了与帕金森病相关的α-突触核蛋白聚集体的传播。这些发现提出了 Clusterin 在阿尔茨海默病中上调与 Tau 病理学进展之间可能存在机制联系的可能性。本文综述了 Clusterin 在神经退行性疾病发病机制中的多种功能，重点介绍了 Clusterin 可能作为病理的抑制剂或增强剂发挥作用的证据。
