Cox Dezerae, Selig Emily, Griffin Michael D W, Carver John A, Ecroyd Heath
From the Illawarra Health and Medical Research Institute and.
School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522.
J Biol Chem. 2016 Oct 21;291(43):22618-22629. doi: 10.1074/jbc.M116.739250. Epub 2016 Sep 1.
The aggregation of α-synuclein (α-syn) into amyloid fibrils is associated with neurodegenerative diseases, collectively referred to as the α-synucleinopathies. In vivo, molecular chaperones, such as the small heat-shock proteins (sHsps), normally act to prevent protein aggregation; however, it remains to be determined how aggregation-prone α-syn evades sHsp chaperone action leading to its disease-associated deposition. This work examines the molecular mechanism by which two canonical sHsps, αB-crystallin (αB-c) and Hsp27, interact with aggregation-prone α-syn to prevent its aggregation in vitro Both sHsps are very effective inhibitors of α-syn aggregation, but no stable complex between the sHsps and α-syn was detected, indicating that the sHsps inhibit α-syn aggregation via transient interactions. Moreover, the ability of these sHsps to prevent α-syn aggregation was dependent on the kinetics of aggregation; the faster the rate of aggregation (shorter the lag phase), the less effective the sHsps were at inhibiting fibril formation of α-syn. Thus, these findings indicate that the rate at which α-syn aggregates in cells may be a significant factor in how it evades sHsp chaperone action in the α-synucleinopathies.
α-突触核蛋白（α-syn）聚集成淀粉样纤维与神经退行性疾病相关，这些疾病统称为α-突触核蛋白病。在体内，分子伴侣，如小热休克蛋白（sHsps），通常起到防止蛋白质聚集的作用；然而，易于聚集的α-syn如何逃避sHsp伴侣作用导致其与疾病相关的沉积仍有待确定。这项工作研究了两种典型的sHsps，即αB-晶状体蛋白（αB-c）和Hsp27，与易于聚集的α-syn相互作用以在体外防止其聚集的分子机制。两种sHsps都是α-syn聚集的非常有效的抑制剂，但未检测到sHsps与α-syn之间形成稳定的复合物，这表明sHsps通过瞬时相互作用抑制α-syn聚集。此外，这些sHsps防止α-syn聚集的能力取决于聚集动力学；聚集速率越快（滞后阶段越短），sHsps抑制α-syn纤维形成的效果就越差。因此，这些发现表明α-syn在细胞中聚集的速率可能是其在α-突触核蛋白病中逃避sHsp伴侣作用的一个重要因素。
