Mechanisms of suppression of α-synuclein neurotoxicity by geldanamycin in Drosophila
Mechanisms of suppression of α-synuclein neurotoxicity by geldanamycin in Drosophila
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DOI：
10.1074/jbc.m412106200
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发表时间：
2005-01-28
影响因子：
4.8
通讯作者：
Bonini, NM
中科院分区：
文献类型：
--
作者：
Auluck, PK;Meulener, MC;Bonini, NM
帕金森氏病是一种常见的神经退行性疾病，其特征在于黑质神经节中多巴胺能神经元的损失和蛋白质α-突触核蛋白积聚成称为路易体和路易神经突的聚集体。帕金森病可以在果蝇中建模，其中α-突触核蛋白的定向表达诱导多巴胺能神经元的妥协和路易体样聚集体的形成。分子伴侣Hsp 70保护细胞免受α-突触核蛋白的有害影响，这表明了一种潜在的治疗方法，以提高帕金森病神经元的存活率。我们现在已经研究了药物格尔德霉素保护神经元免受α-突触核蛋白毒性的分子机制。我们的研究表明，格尔德霉素在正常生理参数范围内使应激反应敏感，以增强伴侣蛋白激活，从而提供针对α-突触核蛋白神经毒性的保护。此外，格尔德霉素将神经元毒性与路易体和路易神经突形成解偶联，使得多巴胺能神经元被保护免受α-突触核蛋白表达的影响，尽管包含病理学持续存在（甚至增加）。这些研究表明，调节应激反应的化合物是治疗帕金森病的一种有前途的方法。
Parkinson's disease is a common neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of the protein alpha-synuclein into aggregates called Lewy bodies and Lewy neurites. Parkinson's disease can be modeled in Drosophila where directed expression of alpha-synuclein induces compromise of dopaminergic neurons and the formation of Lewy body-like aggregates. The molecular chaperone Hsp70 protects cells from the deleterious effects of alpha-synuclein, indicating a potential therapeutic approach to enhance neuron survival in Parkinson's disease. We have now investigated the molecular mechanisms by which the drug geldanamycin protects neurons against alpha-synuclein toxicity. Our studies show that geldanamycin sensitizes the stress response within normal physiological parameters to enhance chaperone activation, offering protection against alpha-synuclein neurotoxicity. Further, geldanamycin uncouples neuronal toxicity from Lewy body and Lewy neurite formation such that dopaminergic neurons are protected from the effects of alpha-synuclein expression despite the continued presence of (and even increase in) inclusion pathology. These studies indicate that compounds that modulate the stress response are a promising approach to treat Parkinson's disease.