Klein Fabrice A C, Pastore Annalisa, Masino Laura, Zeder-Lutz Gabrielle, Nierengarten Hélène, Oulad-Abdelghani Mustapha, Altschuh Danièle, Mandel Jean-Louis, Trottier Yvon
Department of Molecular Pathology, Institut de Génétique et Biologie Moléculaire et Cellulaire, UMR 7104-CNRS/INSERM/ULP, BP10142, 67404 Illkirch Cédex, CU de Strasbourg, France.
J Mol Biol. 2007 Aug 3;371(1):235-44. doi: 10.1016/j.jmb.2007.05.028. Epub 2007 May 18.
Abnormally expanded polyglutamine (polyQ) tracts provide a gain of toxic functions to nine otherwise unrelated human proteins and induce progressive neurodegenerative diseases. Over the past ten years, it was suggested that only polyQ tracts longer than a specific threshold adopt a particular structure, which would be the cause of the apparent polyQ length-dependent toxicity threshold observed in polyQ diseases. We have used a combination of biochemical and biophysical approaches to compare the structural properties of polyQ of pathogenic and non-pathogenic lengths under various conditions. We observe that pathogenic and non-pathogenic polyQ, as soluble species and upon interaction with a partner, during aggregation, or as mature aggregates, display very similar structural properties. PolyQ length only influences the aggregation kinetics and, to a lesser extent, the stability of the aggregates. We thus propose that polyQ toxicity does not depend on a structural transition occurring above a specific threshold, but rather that polyQ tracts are inherently toxic sequences, whose deleterious effect gradually increases with their length. We discuss how polyQ properties and other cellular factors may explain the existence of an apparent polyQ length-dependent toxicity threshold.
异常扩展的聚谷氨酰胺（polyQ）片段会赋予九种原本不相关的人类蛋白质毒性功能，并引发进行性神经退行性疾病。在过去十年中，有人提出只有长度超过特定阈值的polyQ片段才会呈现特定结构，这可能是在polyQ疾病中观察到明显的polyQ长度依赖性毒性阈值的原因。我们结合了生化和生物物理方法，比较了在各种条件下致病长度和非致病长度的polyQ的结构特性。我们观察到，致病和非致病的polyQ，无论是作为可溶形式、与伴侣相互作用时、聚集过程中还是作为成熟聚集体，都表现出非常相似的结构特性。PolyQ长度仅影响聚集动力学，并在较小程度上影响聚集体的稳定性。因此，我们提出polyQ毒性并不取决于在特定阈值以上发生的结构转变，而是polyQ片段本身就是有毒序列，其有害作用会随着长度的增加而逐渐增强。我们讨论了polyQ特性和其他细胞因素如何解释明显的polyQ长度依赖性毒性阈值的存在。
