Eyal Allon, Engelender Simone
Department of Pharmacology, The B. Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa, Israel.
Cell Cycle. 2006 Sep;5(18):2082-6. doi: 10.4161/cc.5.18.3209. Epub 2006 Sep 15.
A common finding in many neurodegenerative diseases is the presence of inclusion bodies made of aggregated proteins in neurons of affected brain regions. In Parkinson's disease, the inclusion bodies are referred to as Lewy bodies and their main component is alpha-synuclein. Although many studies have suggested that inclusion bodies may be cell protective, it is still not clear whether Lewy bodies promote or inhibit dopaminergic cell death in Parkinson's disease. Synphilin-1 interacts with alpha-synuclein and is present in Lewy bodies. Accumulation of ubiquitylated synphilin-1 leads to massive formation of inclusion bodies, which resemble Lewy bodies by their ability to recruit alpha-synuclein. We have recently isolated an isoform of synphilin-1, synphilin-1A, that spontaneously aggregates in cells, and is present in detergent-insoluble fractions of brain protein samples from alpha-synucleinopathy patients. Synphilin-1A displays marked neuronal toxicity and, upon proteasome inhibition, accumulates into ubiquitylated inclusions with concomitant reduction of its intrinsic toxicity. The fact that alpha-synuclein interacts with synphilin-1A, and is recruited to synphilin-1A inclusion bodies in neurons together with synphilin-1, further indicates that synphilin-1A cell model is relevant for research on Parkinson's disease. Synphilin-1A cell model may help provide important insights regarding the role of inclusion bodies in Parkinson's disease and other neurodegenerative disorders.
在许多神经退行性疾病中常见的一个现象是，在受影响脑区的神经元中存在由聚集蛋白构成的包涵体。在帕金森病中，这些包涵体被称为路易小体，其主要成分是α-突触核蛋白。尽管许多研究表明包涵体可能具有细胞保护作用，但路易小体在帕金森病中是促进还是抑制多巴胺能细胞死亡仍不清楚。突触核蛋白-1与α-突触核蛋白相互作用，并存在于路易小体中。泛素化的突触核蛋白-1的积累导致包涵体大量形成，这些包涵体通过招募α-突触核蛋白的能力而类似于路易小体。我们最近分离出了突触核蛋白-1的一种异构体，即突触核蛋白-1A，它在细胞中自发聚集，并存在于α-突触核蛋白病患者脑蛋白样品的去污剂不溶性组分中。突触核蛋白-1A表现出明显的神经元毒性，并且在蛋白酶体抑制后，积累形成泛素化包涵体，同时其内在毒性降低。α-突触核蛋白与突触核蛋白-1A相互作用，并与突触核蛋白-1一起被招募到神经元中的突触核蛋白-1A包涵体中，这一事实进一步表明突触核蛋白-1A细胞模型与帕金森病的研究相关。突触核蛋白-1A细胞模型可能有助于提供关于包涵体在帕金森病和其他神经退行性疾病中的作用的重要见解。
