Beyer Katrin, Domingo-Sàbat Montserrat, Humbert Jordi, Carrato Cristina, Ferrer Isidro, Ariza Aurelio
Department of Pathology, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, Barcelona, Spain.
Neurogenetics. 2008 Jul;9(3):163-72. doi: 10.1007/s10048-008-0124-6. Epub 2008 Mar 12.
Alpha-synuclein, parkin, and synphilin-1 are proteins mainly involved in the pathogenesis of Lewy body (LB) diseases. mRNAs of all three undergo alternative splicing, so that the existence of various isoforms has been described. Since increasing evidence supports the importance of differential isoform-expression changes in disease development, we have established isoform-expression profiles in frontal cortices of LB disease brains in comparison with those of Alzheimer disease (AD) and control frontal cortices. The differential expression of four alpha-synuclein, seven parkin, and four synphilin-1 isoforms was ascertained by the use of isoform-specific primers and relative expression analysis with SybrGreen and beta-actin as an internal standard. The establishment of isoform-expression profiles revealed that these are disease specific. Moreover, isoform-expression deregulation of mainly one gene in each disease could be observed. All four alpha-synuclein isoforms were affected in the case of the pure form of dementia with LB, most parkin transcript variants in common LB disease, and all synphilin-1 isoforms in Parkinson disease. Only minor involvement was detected in AD. Finally, the existence of a proprietary isoform-expression profile in common LB disease indicates that this disease develops as a result of its own molecular mechanisms, and so, at the molecular level, it does not exactly share changes found in pure dementia with LB and AD. In conclusion, isoform-expression profiles in LB diseases represent additional evidence for the direct involvement of isoform-expression deregulation in the development of neurodegenerative disorders.
α-突触核蛋白、帕金蛋白和突触结合蛋白-1是主要参与路易体（LB）疾病发病机制的蛋白质。这三种蛋白的信使核糖核酸（mRNA）均会发生可变剪接，因此已有多种亚型存在的描述。由于越来越多的证据支持不同亚型表达变化在疾病发展中的重要性，我们已建立了LB疾病脑额叶皮质中的亚型表达谱，并与阿尔茨海默病（AD）和对照额叶皮质进行比较。通过使用亚型特异性引物以及以SybrGreen和β-肌动蛋白作为内参的相对表达分析，确定了四种α-突触核蛋白、七种帕金蛋白和四种突触结合蛋白-1亚型的差异表达。亚型表达谱的建立表明这些是疾病特异性的。此外，在每种疾病中均可观察到主要一个基因的亚型表达失调。在纯路易体痴呆病例中，所有四种α-突触核蛋白亚型均受影响；在常见的LB疾病中，大多数帕金转录变体受影响；在帕金森病中，所有突触结合蛋白-1亚型均受影响。在AD中仅检测到轻微受累。最后，常见LB疾病中存在独特的亚型表达谱表明该疾病是由其自身的分子机制发展而来，因此，在分子水平上，它与纯路易体痴呆和AD中发现的变化并不完全相同。总之，LB疾病中的亚型表达谱为亚型表达失调直接参与神经退行性疾病的发展提供了额外证据。
