Aggregated α-synuclein mediates dopaminergic neurotoxicity in vivo
Aggregated α-synuclein mediates dopaminergic neurotoxicity in vivo
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DOI：
10.1523/jneurosci.0285-07.2007
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发表时间：
2007-03-21
影响因子：
5.3
通讯作者：
Feany, Mel B.
中科院分区：
文献类型：
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作者：
Periquet, Magali;Fulga, Tudor;Feany, Mel B.
突触蛋白α-突触核蛋白的突变导致罕见的遗传形式的帕金森病。α-突触核蛋白也被认为在更常见的帕金森病的散发病例中起关键作用，因为该蛋白质聚集在该疾病的标志性神经元内包涵体Lewy小体中。为了测试蛋白质聚集在帕金森病发病机制中的作用，我们表达了一种缺失氨基酸71-82的α-突触核蛋白形式，其在该疾病的转基因果蝇模型中不能在体外聚集。我们在这些动物中没有发现α-突触核蛋白的大聚集体或寡聚体的证据，也没有酪氨酸羟化酶阳性神经元的损失。我们还表达了截短形式的α-突触核蛋白，其具有增强的体外聚集能力。这种截短形式的α-突触核蛋白显示出聚集成大包涵体的增加，高分子量α-突触核蛋白物质的积累增加，并显示出体内神经毒性增强。因此，我们的研究结果支持α-突触核蛋白的聚集在介导体内多巴胺能神经元毒性中的关键作用，尽管α-突触核蛋白的每种聚集形式在神经毒性中发挥的确切作用仍有待确定。
Mutations in the synaptic protein alpha-synuclein cause rare genetic forms of Parkinson's disease. alpha-Synuclein is thought to play a critical role in more common sporadic cases of Parkinson's disease as well because the protein aggregates in the hallmark intraneuronal inclusions of the disorder, Lewy bodies. To test the role of protein aggregation in the pathogenesis of Parkinson's disease, we expressed a form of alpha-synuclein with a deletion of amino acids 71-82 that is unable to aggregate in vitro in a transgenic Drosophila model of the disorder. We found no evidence of large aggregates or oligomeric species of alpha-synuclein in these animals and no loss of tyrosine hydroxylase- positive neurons. We also expressed a truncated form of alpha-synuclein that has enhanced ability to aggregate in vitro. This truncated form of alpha-synuclein showed increased aggregation into large inclusions bodies, increased accumulation of high molecular weight alpha-synuclein species, and demonstrated enhanced neurotoxicity in vivo. Our findings thus support a critical role for aggregation of alpha-synuclein in mediating toxicity to dopaminergic neurons in vivo, although the precise role each aggregated form of alpha-synuclein plays in neurotoxicity remains to be determined.