Synphilin isoforms and the search for a cellular model of Lewy body formation in Parkinson's disease
Synphilin isoforms and the search for a cellular model of Lewy body formation in Parkinson's disease
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DOI：
10.4161/cc.5.18.3209
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发表时间：
2006-09-15
期刊：
影响因子：
4.3
通讯作者：
Engelender, Simone
中科院分区：
文献类型：
--
作者：
Eyal, Allon;Engelender, Simone
在许多神经退行性疾病中的一个常见发现是在受影响的脑区域的神经元中存在由聚集的蛋白质制成的包涵体。在帕金森氏病中，包涵体被称为路易体，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，但路易体是否促进或抑制帕金森病中多巴胺能细胞死亡仍不清楚。Synphilin-1与α-突触核蛋白相互作用并存在于路易体中。泛素化的突触亲蛋白-1的积累导致包涵体的大量形成，包涵体通过其募集α-突触核蛋白的能力而类似于路易体。我们最近分离出一种突触亲蛋白-1的亚型，突触亲蛋白-1A，它在细胞中自发聚集，并且存在于α-突触核蛋白病患者脑蛋白样品的洗涤剂不溶性部分中。Synphilin-1A显示出明显的神经元毒性，并且在蛋白酶体抑制后，积累成泛素化的包涵体，伴随着其内在毒性的降低。α-突触核蛋白与突触亲蛋白-1A相互作用，并与突触亲蛋白-1一起被募集到神经元中的突触亲蛋白-1A包涵体，这一事实进一步表明突触亲蛋白-1A细胞模型与帕金森病的研究相关。Synphilin-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。
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.