Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Department of Experimental Neurodegeneration, University Medical Center Göttingen, 37073 Göttingen, Germany.
Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):E4971-E4977. doi: 10.1073/pnas.1700200114. Epub 2017 Jun 5.
Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson's disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson's disease-related proteins-α-synuclein, LRRK2, and Parkin-α-synuclein might be a major link. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death. Because this detrimental effect of α-synuclein on neurons can be rescued by the small molecule anle138b, we explored its effect on melanoma cells. We found that treatment with anle138b leads to massive melanoma cell death due to a major dysregulation of autophagy, suggesting that α-synuclein is highly beneficial to advanced melanoma because it ensures that autophagy is maintained at a homeostatic level that promotes and ensures the cell's survival.
最近的流行病学和临床研究报告称，帕金森病患者患黑色素瘤的风险显著增加。由于没有证据表明遗传因素是这两种疾病之间关联的原因，我们假设在三种主要的帕金森病相关蛋白——α-突触核蛋白、LRRK2 和 Parkin-α-突触核蛋白中，α-突触核蛋白可能是主要的联系。我们在这里提出的研究数据表明，α-突触核蛋白促进原发性和转移性黑色素瘤细胞的存活，这与 α-突触核蛋白对多巴胺能神经元的作用完全相反，α-突触核蛋白在多巴胺能神经元中的积累会导致神经元功能障碍和死亡。因为小分子 anle138b 可以挽救 α-突触核蛋白对神经元的这种有害作用，所以我们探索了它对黑色素瘤细胞的作用。我们发现，由于自噬的严重失调，anle138b 的治疗导致大量黑色素瘤细胞死亡，这表明 α-突触核蛋白对晚期黑色素瘤非常有益，因为它确保自噬维持在促进和确保细胞存活的生理平衡水平。
