Divergent effects of the H5OQ and G51D SNCA mutations on the aggregation of α-synuclein
Divergent effects of the H5OQ and G51D SNCA mutations on the aggregation of α-synuclein
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DOI：
10.1111/jnc.12806
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发表时间：
2014-12-01
影响因子：
4.7
通讯作者：
Giasson, Benoit I.
中科院分区：
文献类型：
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作者：
Rutherford, Nicola J.;Moore, Brenda D.;Giasson, Benoit I.
SNCA突变的发现是开创性的发现，使人们了解到-突触核蛋白(S)是帕金森氏病相关路易体的主要成分。由于这些蛋白质包涵体和SNCA突变的病理作用尚未完全确定，我们表征了最近发现的SNCA突变H50Q和G51D的聚集特性，以提供新的见解。用反式、trans)-1-bromo-2，5-bis-(4-hydroxy)styrylbenzene荧光、沉降法、电子显微镜和原子力显微镜研究了重组H50Q、G51D和野生型S的聚合和聚集形成淀粉样蛋白的性质。这些研究表明，H50Q突变使S聚集率增加，而G51D突变则相反。然而，在促进H50Q和G51D S进入细胞的条件下，外源淀粉样变种子仍然可以类似地诱导它们形成细胞内聚集体。两个突变体S蛋白，尤其是G51D，在细胞应激条件下都促进了细胞毒性。这些发现表明，新的致病性SNCA突变H50Q和G51D对聚集特性的影响与野生型蛋白不同，G51D S表现出聚集减少，尽管发病较早，这表明这些突变促进了S发病的不同机制。
The discoveries of mutations in SNCA were seminal findings that resulted in the knowledge that -synuclein (S) is the major component of Parkinson's disease-associated Lewy bodies. Since the pathologic roles of these protein inclusions and SNCA mutations are not completely established, we characterized the aggregation properties of the recently identified SNCA mutations, H50Q and G51D, to provide novel insights. The properties of recombinant H50Q, G51D, and wild-type S to polymerize and aggregate into amyloid were studied using (trans,trans)-1-bromo-2,5-bis-(4-hydroxy)styrylbenzene fluorometry, sedimentation analyses, electron microscopy, and atomic force microscopy. These studies showed that the H50Q mutation increases the rate of S aggregation, whereas the G51D mutation has the opposite effect. However, H50Q and G51D S could still be similarly induced to form intracellular aggregates from the exposure to exogenous amyloidogenic seeds under conditions that promote their cellular entry. Both mutant S proteins, but especially G51D, promoted cellular toxicity under cellular stress conditions. These findings reveal that the novel pathogenic SNCA mutations, H50Q and G51D, have divergent effects on aggregation properties relative to the wild-type protein, with G51D S demonstrating reduced aggregation despite presenting with earlier disease onset, suggesting that these mutants promote different mechanisms of S pathogenesis.