Meriin A B, Sherman M Y
Department of Biochemistry, Boston University Medical School, MA, USA.
Int J Hyperthermia. 2005 Aug;21(5):403-19. doi: 10.1080/02656730500041871.
Many major neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington Disease and other polyglutamine expansion disorders, are associated with degeneration and death of specific neuronal populations due to accumulation of certain abnormal polypeptides. These misfolded species aggregate and form inclusion bodies and their neurotoxicity is associated with the aggregation. To handle a build-up of abnormal proteins cells employ a complicated machinery of molecular chaperones and various proteolytic systems. Chaperones facilitate refolding or degradation of misfolded polypeptides, prevent protein aggregation and play a role in formation of aggresome, a centrosome-associated body to which small cytoplasmic aggregates are transported. The ubiquitin-proteasome proteolytic system is critical for reducing the levels of soluble abnormal proteins, while autophagy plays the major role in clearing of cells from protein aggregates. Accumulation of the aggregation prone proteins activates signal transduction pathways that control cell death, including JNK pathway that controls viability of a cell in various models of Parkinson's and Huntington's diseases. The major chaperone Hsp72 can interfere with this signalling pathway, thus promoting survival. A very important consequence of a build-up and aggregation of misfolded proteins is impairment of the ubiquitin-proteasome degradation system and suppression of the heat shock response. Such an inhibition of the major cell defense systems may play a critical role in neurodegeneration. Here, it is suggested that these changes may reflect a senescence-like programme initiated by the aggregated abnormal polypeptides. Pathways that control the fate of misfolded proteins, for example molecular chaperones or proteolytic systems, may become interesting novel targets for therapy of neurodegenerative disorders.
许多主要的神经退行性疾病，包括肌萎缩侧索硬化症、阿尔茨海默病、帕金森病、亨廷顿病以及其他多聚谷氨酰胺扩增障碍疾病，都与特定神经元群体的退化和死亡有关，这是由于某些异常多肽的积累所致。这些错误折叠的蛋白质聚集并形成包涵体，其神经毒性与聚集有关。为了应对异常蛋白质的积累，细胞利用分子伴侣和各种蛋白水解系统组成的复杂机制。分子伴侣促进错误折叠多肽的重新折叠或降解，防止蛋白质聚集，并在聚集体的形成中发挥作用，聚集体是一种与中心体相关的结构，小的细胞质聚集体会被转运到此处。泛素 - 蛋白酶体蛋白水解系统对于降低可溶性异常蛋白质的水平至关重要，而自噬在清除细胞内蛋白质聚集体方面起主要作用。易于聚集的蛋白质的积累会激活控制细胞死亡的信号转导通路，包括在帕金森病和亨廷顿病的各种模型中控制细胞活力的JNK通路。主要的分子伴侣Hsp72可以干扰这条信号通路，从而促进细胞存活。错误折叠蛋白质的积累和聚集的一个非常重要的后果是泛素 - 蛋白酶体降解系统受损以及热休克反应受到抑制。这种对主要细胞防御系统的抑制可能在神经退行性变中起关键作用。在此，有人提出这些变化可能反映了由聚集的异常多肽引发的类似衰老的程序。控制错误折叠蛋白质命运的通路，例如分子伴侣或蛋白水解系统，可能成为神经退行性疾病治疗中有趣的新靶点。
