Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, London, UK.
Trends Mol Med. 2010 Jan;16(1):27-36. doi: 10.1016/j.molmed.2009.11.004. Epub 2009 Dec 24.
Several neurodegenerative diseases, including Parkinson's disease (PD) are associated with protein misfolding and the formation of distinct aggregates, resulting in a putative pathological protein load on the nervous system. A variety of factors cause proteins to aggregate, including aggregation-prone sequences, specific mutations, protein modifications and also dysregulation of the protein degradation machinery. Molecular chaperones are responsible for maintaining normal protein homeostasis within the cell by assisting protein folding and modulating protein-degrading pathways. Here, we review the fundamental mechanisms of neurodegeneration occurring in PD involving alpha-synuclein fibrillisation and aggregation, endoplasmic reticulum stress, ubiquitin proteasome systems, autophagy and lysosomal degradation. Molecular chaperones serve a neuroprotective role in many of these pathways, and we discuss recent evidence indicating that these proteins might provide the basis for new therapeutic approaches.
几种神经退行性疾病，包括帕金森病（PD），与蛋白质错误折叠和形成不同的聚集体有关，导致神经系统存在潜在的病理性蛋白负荷。许多因素会导致蛋白质聚集，包括易于聚集的序列、特定的突变、蛋白质修饰以及蛋白质降解机制的失调。分子伴侣通过协助蛋白质折叠和调节蛋白质降解途径，负责维持细胞内正常的蛋白质动态平衡。在这里，我们综述了 PD 中涉及α-突触核蛋白纤维形成和聚集、内质网应激、泛素蛋白酶体系统、自噬和溶酶体降解的神经退行性变的基本机制。分子伴侣在这些途径中的许多方面发挥神经保护作用，我们讨论了最近的证据表明这些蛋白质可能为新的治疗方法提供基础。
