Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
Antioxid Redox Signal. 2009 Sep;11(9):2119-34. doi: 10.1089/ars.2009.2490.
Protein aggregation as a result of misfolding is a common theme underlying neurodegenerative diseases. In Parkinson's disease (PD), research on protein misfolding and aggregation has taken center stage following the association of alpha-synuclein gene mutations with familial forms of the disease, and importantly, the identification of the protein as a major component of Lewy bodies, a pathological hallmark of PD. Fueling this excitement is the subsequent identification of another PD-linked gene, parkin, as a ubiquitin ligase associated with the proteasome, a major intracellular protein degradation machinery that destroys unwanted, albeit mainly soluble, proteins. Notably, a role for parkin in the clearance of insoluble protein aggregates via macroautophagy has also been implicated by more recent studies. Paradoxically, like alpha-synuclein, parkin is also prone to misfolding, especially in the presence of age-related stress. Similarly, protein misfolding can also affect the function of other key PD-linked genes such as DJ-1, PINK1, and perhaps also LRRK2. Here, we discuss the role of protein misfolding and aggregation in PD, and how impairments of the various cellular protein quality systems could precipitate these events and lead to neuronal demise. Towards the end of our discussion, we also revisited the role of Lewy body formation in PD.
蛋白质错误折叠导致的聚集是神经退行性疾病的一个常见主题。在帕金森病 (PD) 中，随着与家族性疾病相关的α-突触核蛋白基因突变的发现，以及重要的是，该蛋白被确定为路易体的主要成分，即 PD 的病理标志，对蛋白质错误折叠和聚集的研究成为焦点。这一兴奋点源于另一个与 PD 相关的基因 parkin 的发现，它是一种与蛋白酶体相关的泛素连接酶，蛋白酶体是一种主要的细胞内蛋白质降解机制，可破坏不需要的、尽管主要是可溶性的蛋白质。最近的研究表明，parkin 在通过巨自噬清除不溶性蛋白质聚集体方面也发挥作用。矛盾的是，像α-突触核蛋白一样，parkin 也容易错误折叠，尤其是在存在与年龄相关的应激时。同样，蛋白质错误折叠也会影响其他关键的 PD 相关基因，如 DJ-1、PINK1，也许还有 LRRK2。在这里，我们讨论了蛋白质错误折叠和聚集在 PD 中的作用，以及各种细胞蛋白质质量系统的损伤如何引发这些事件并导致神经元死亡。在我们讨论的最后，我们还重新审视了路易体形成在 PD 中的作用。
