Comprehensive Movement Disorders Center, University at Buffalo, 3435 Main Street, 97 Farber Hall, Buffalo, NY 14214, United States.
Med Hypotheses. 2019 Oct;131:109302. doi: 10.1016/j.mehy.2019.109302. Epub 2019 Jul 4.
Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. β-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. β-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and β-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, β-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of β-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 β (GSK-3β). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3β inhibition and consequent enhanced β-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect β-catenin-mediated activity and slow disease progression in patients with PD or melanoma.
帕金森病 (PD) 患者黑色素瘤发病率较高，反之亦然，这表明这两种疾病可能具有共同的发病途径。β-连环蛋白是一种转录共因子，当集中在核内时，可上调经典 Wnt 靶基因的表达，如 Nurr1，其中许多基因对神经元的存活很重要。β-连环蛋白介导的活性在散发性 PD 以及富亮氨酸重复激酶 2 (LRRK2) 和β-葡萄糖苷酶 (GBA) 突变 PD 细胞模型中降低，LRRK2 和 GBA 分别是 PD 最常见的遗传原因和风险因素。此外，β-连环蛋白的表达在侵袭性更强和转移性黑色素瘤中显著降低。多项观察性研究表明，吸烟者 PD 和黑色素瘤的发病率明显较低，这表明烟草可能含有一种或多种元素，可以预防这两种疾病。支持这一观点的是，吸烟者的大脑中α-突触核蛋白的水平显著降低，α-突触核蛋白是 PD 大脑和黑色素瘤细胞中发现的一种病理性细胞内蛋白。与其他植物相比，烟草中含有非常高的锂水平。锂具有广泛的神经保护作用，包括增强自噬和降低细胞内α-突触核蛋白水平，并且在神经毒素和转基因 PD 动物模型中均有效。锂的神经保护作用之一是增强β-连环蛋白介导的活性，通过抑制糖原合酶激酶-3β (GSK-3β) 来增加 Nurr1 的表达。锂对黑色素瘤细胞也有抗增殖作用，锂的临床应用与黑色素瘤发病率降低以及黑色素瘤相关死亡率降低有关。这是第一个假设，即吸烟吸入的锂可能导致 PD 和黑色素瘤发病率降低，这种保护可能部分通过锂诱导的 GSK-3β 抑制和随后增强的β-连环蛋白介导的活性来介导。这一假说可以在临床试验中直接进行测试，评估锂治疗对 PD 或黑色素瘤患者β-连环蛋白介导的活性和疾病进展的影响。
