Department of Structural Biology and the Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
Department of Structural Biology and the Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
J Biol Chem. 2014 Apr 11;289(15):10254-10260. doi: 10.1074/jbc.C114.552943. Epub 2014 Mar 4.
There are now 10 expanded CAG repeat diseases in which both disease risk and age of onset are strongly dependent on the repeat length of the polyglutamine (polyQ) sequence in the disease protein. Large, polyQ-rich inclusions in patient brains and in cell and animal models are consistent with the involvement of polyQ aggregation in the disease mechanism. This possibility is reinforced by studies showing strong repeat length dependence to the aggregation process, qualitatively mirroring the repeat length dependence of disease risk. Our understanding of the underlying biophysical principles that mediate the repeat length dependence of aggregation, however, is far from complete. A previous study of simple polyQ peptides showed that N*, the size of the critical nucleus that controls onset of aggregation, decreases from unfavorable tetramer to favorable monomer over the range Q23 to Q26. These data, however, do not explain why, for all peptides exhibiting N* ∼ 1, spontaneous aggregation rates continue to increase with increasing repeat length. Here we describe a novel kinetics analyses that maps out the nonlinear dependence with repeat length of a nucleation efficiency term that is likely related to aspects of nucleus structure. This trend accounts for why nucleus size increases to tetrameric at repeat lengths of Q23 or below. Intriguingly, both aggregation and age of onset trend with repeat length in similar ways, exhibiting large changes per added Gln at low repeat lengths and small changes per added Gln at relatively long repeat lengths. Fibril stability also increases with repeat length in a nonlinear fashion.
现在有 10 种扩展的 CAG 重复疾病，其中疾病风险和发病年龄强烈依赖于疾病蛋白中多聚谷氨酰胺（polyQ）序列的重复长度。患者大脑以及细胞和动物模型中的大的、富含 polyQ 的包涵体与 polyQ 聚集在疾病机制中的参与一致。这一可能性得到了研究的支持，这些研究表明聚合过程对重复长度有很强的依赖性，这在定性上反映了疾病风险对重复长度的依赖性。然而，我们对介导聚合的重复长度依赖性的基本生物物理原理的理解还远远不够。先前对简单 polyQ 肽的研究表明，控制聚合起始的临界核 N*，从不利的四聚体减小到有利的单体，范围从 Q23 到 Q26。然而，这些数据并不能解释为什么对于所有表现出 N*∼1 的肽，自发聚合速率继续随着重复长度的增加而增加。在这里，我们描述了一种新的动力学分析，该分析描绘了与核结构方面相关的成核效率项的非线性重复长度依赖性。这一趋势解释了为什么核大小在重复长度为 Q23 或以下时增加到四聚体。有趣的是，聚集和发病年龄以相似的方式随重复长度变化，在低重复长度时每增加一个 Gln 就会发生很大的变化，而在相对较长的重复长度时每增加一个 Gln 就会发生很小的变化。纤维稳定性也以非线性方式随重复长度增加。
