Molecular crowding accelerates fibrillization of α-synuclein:: Could an increase in the cytoplasmic protein concentration induce Parkinson's disease?
Molecular crowding accelerates fibrillization of α-synuclein:: Could an increase in the cytoplasmic protein concentration induce Parkinson's disease?
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DOI：
10.1021/bi0120906
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发表时间：
2002-03-26
期刊：
影响因子：
2.9
通讯作者：
Lansbury, PT
中科院分区：
文献类型：
--
作者：
Shtilerman, MD;Ding, TT;Lansbury, PT
帕金森病 (PD) 是许多神经退行性疾病之一，其特征是淀粉样原纤维形成。 α-突触核蛋白是纤维状神经元包涵体（称为路易体）的主要成分，可诊断 PD。此外，α-突触核蛋白基因与家族性帕金森病有关。 α-突触核蛋白通过离散的富含 β 片层的寡聚体或原纤维形成原纤维，这些寡聚体随着原纤维的生长而被消耗。两种 FPD 突变都会加速原纤维的形成，表明这些中间体而不是原纤维产物会引发神经元损失。在特发性 PD 中，其他因素可能导致野生型 α-突触核蛋白加速原纤维形成。一种可能的因素可能是神经元细胞质中的分子拥挤。我们在此证明，使用惰性聚合物的拥挤显着减少了原纤维形成和原纤维转化为原纤维的滞后时间，但不影响任一物种的形态。体外拥挤程度的生理现实变化具有显着的动力学后果。因此，由细胞体积变化和/或蛋白质降解改变引起的总细胞质蛋白质浓度的非特异性变化可以促进α-突触核蛋白原纤维的形成和稳定。
Parkinson's disease (PD) is one of many neurodegenerative diseases that are characterized by amyloid fibril formation. alpha-Synuclein is a primary component of the fibrillar neuronal inclusions, known as Lewy bodies, that are diagnostic of PD. In addition, the alpha-synuclein gene is linked to familial PD. Fibril formation by alpha-synuclein proceeds via discrete beta-sheet-rich oligomers, or protofibrils, that are consumed as fibrils grow. Both FPD mutations accelerate formation of protofibrils, suggesting that these intermediates, rather than the fibril product, trigger neuronal loss. In idiopathic PD, other factors may be responsible for accelerating protofibril formation by wild-type alpha-synuclein. One possible factor could be molecular crowding in the neuronal cytoplasm. We demonstrate here that crowding using inert polymers significantly reduced the lag time for protofibril formation and the conversion of the protofibril to the fibril, but did not affect the morphology of either species. Physiologically realistic changes in the degree of in vitro crowding have significant kinetic consequences. Thus, nonspecific changes in the total cytoplasmic protein concentration, induced by cell volume changes and/or altered protein degradation, could promote formation of and stabilize the alpha-synuclein protofibril.