Michalik Andrej, Van Broeckhoven Christine
Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium.
Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R173-86. doi: 10.1093/hmg/ddg295.
Expansion of CAG trinucleotide repeats coding for polyglutamine in unrelated proteins causes at least nine late-onset progressive neurodegenerative disorders, including Huntington's disease and a number of spinocerebellar ataxias. Expanded polyglutamine provokes a dominant gain-of-function neurotoxicity, regardless of the specific protein context within which it resides. Nevertheless, the protein context does modulate polyglutamine toxicity, as evidenced by the distinct clinical and pathological features of the various disorders. Importantly, polyglutamine toxicity might derive from its ability to aggregate. Indeed, aggregation probably underlies some defining attributes of the polyglutamine disorders, such as their late onset, progressive nature, and the dependence of onset age on polyglutamine length. However, the central role of aggregation in polyglutamine pathogenesis has been challenged by several studies, which instead argued that the soluble form of the disease proteins is responsible for neuronal damage. Thus, the question whether polyglutamine aggregates are deleterious, harmless or protective remains the most passionately disputed issue in the study of these diseases. In this review, we attempt to reconcile some of these controversies.
在不相关蛋白质中编码多聚谷氨酰胺的CAG三核苷酸重复序列的扩增会导致至少九种迟发性进行性神经退行性疾病，包括亨廷顿舞蹈症和多种脊髓小脑共济失调。无论扩展的多聚谷氨酰胺存在于何种特定蛋白质环境中，都会引发显性功能获得性神经毒性。然而，蛋白质环境确实会调节多聚谷氨酰胺毒性，各种疾病不同的临床和病理特征就证明了这一点。重要的是，多聚谷氨酰胺毒性可能源于其聚集能力。事实上，聚集可能是多聚谷氨酰胺疾病一些典型特征的基础，比如它们的迟发性、进行性以及发病年龄对多聚谷氨酰胺长度的依赖性。然而，聚集在多聚谷氨酰胺发病机制中的核心作用受到了几项研究的质疑，这些研究反而认为疾病蛋白的可溶性形式是造成神经元损伤的原因。因此，多聚谷氨酰胺聚集体是有害、无害还是具有保护作用的问题，仍然是这些疾病研究中争议最大的问题。在这篇综述中，我们试图调和其中的一些争议。
