MC1R basis of melanoma-Parkinson's link and neuroprotective potential of MC1R

项目总结/摘要 帕金森病（PD）患者通常患癌症的风险较低，但有一个明显的例外- 黑素瘤PD患者更有可能发展为黑色素瘤，而黑色素瘤患者更容易发生 发展PD的风险更高。这种双向联系不仅在患者身上观察到， 它们的亲戚，这表明这两个看似不同的过程有共同的生物成分。黑色素瘤是 与红头发/白皮肤密切相关，黑皮质素1受体功能丧失多态性的表型 基因（MC 1 R）。我们以前曾报道过红头发的人和红头发的人有更大的PD风险。 携带一辆红头发的MC 1 R变种车携带MC 1 R失活突变的正常黑色（C57 B1/6）小鼠 （MC 1 Re/e小鼠）模仿红发人，因为它们显示红色/黄色褐黑素色素沉着， 褐黑素依赖性氧化性皮肤损伤和黑色素瘤易感性。这些红毛老鼠还表现出 基础条件下的氧化性脑损伤和多巴胺能缺乏， 包括α-突触核蛋白（α-syn）在内的PD模型中的毒性。MC 1 R在小鼠多巴胺能神经元中表达 黑质MC 1 R的存在也已初步证明在黑质的黑质， 人脑，散发性PD患者中信号减少，与多巴胺能神经元丢失相关。 此外，红头发个体中较高的PD相关死亡率已初步证实， 人类队列这一跨学科项目的总体目标是进一步阐明黑色素瘤相关的 PD中的MC 1 R和通过研究动物模型和人群靶向MC 1 R的神经保护潜力 三个具体目标（SA）。SA 1将确定红色色素沉着是否是导致 红头发多巴胺能缺陷和黑质纹状体多巴胺能细胞中是否需要MC 1 R 多巴胺能的完整性SA 2将确定现有MC 1 R激动剂激活MC 1 R是否能保护 针对α-syn神经毒性以及保护是否是MC 1 R特异性的。SA 3将分析红头发和 黑色素瘤风险MC 1 R变体与健康人群发生PD的风险增加相关， 相同的变异是否与那些已经接受过 诊断为PD。建立在流行病学和生物学证据的基础上， 通过跨学科的专业知识，拟议的研究预计将建立因果关系的生物学可解释性。 MC 1 R（和褐黑素）和PD的基础，因此提供了对PD-黑色素瘤关联的见解。其 这些发现将具有高度的转化意义，可能对PD治疗产生重大影响， 我们对帕金森病的流行病学和病理生理学的理解。 .

Project Summary/Abstract Parkinson's disease (PD) patients generally are at lower risk of developing cancers, with one notable exception – melanoma. Individuals with PD are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing PD. This bidirectional link has been observed not only in patients themselves but also in their relatives, suggesting shared biological components of the two seemingly disparate processes. Melanoma is strongly tied to red hair/fair skin, the phenotype of loss-of-function polymorphisms in the melanocortin 1 receptor gene (MC1R). We have previously reported greater PD risk in individuals with red hair color and individuals carrying a redhead MC1R variant. Normally black (C57Bl/6) mice carrying an inactivating mutation of MC1R (MC1Re/e mice) mimic redhead humans, as they display red/yellow pheomelanin pigmentation and pheomelanin-dependent oxidative skin damage and melanoma predisposition. These redhead mice also exhibit oxidative brain damage and dopaminergic deficiency under basal conditions and exacerbated dopaminergic toxicity in models of PD including α-synuclein (α-syn). MC1R is expressed in dopaminergic neurons of the mouse substantia nigra. The presence of MC1R has also been preliminarily demonstrated in the substantia nigra of the human brain, with reduced signal in sporadic PD patients that correlates to loss of dopaminergic neurons. Further, higher PD-associated mortality among redhead individuals has been preliminarily demonstrated in human cohorts. The overall goal of this interdisciplinary project is to further elucidate role of the melanoma-linked MC1R in PD and neuroprotective potential of targeting MC1R by studying animal models and human populations in parallel via three Specific Aims (SAs). SA1 will determine whether red pigmentation is responsible for the redhead dopaminergic deficit and whether MC1R in catecholaminergic cells is required for nigrostriatal dopaminergic integrity. SA2 will determine whether MC1R activation by existing MC1R agonists protects against α-syn neurotoxicity and whether the protection is MC1R-specific. SA3 will analyze whether redhair and melanoma risk MC1R variants are associated with increased risk of developing PD in healthy populations and whether the same variants are associated with faster clinical progression in those who have already been diagnosed with PD. Built on the strength of epidemiological and biological evidence and backed by exceptional expertise across disciplines, the proposed study is expected to establish the biological plausibility of a causal basis for MC1R (and pheomelanin) and PD and therefore to provide insight into PD-melanoma association. Its findings will be of high translational significance with the potential for major impact on PD therapeutics as well as on our understanding of the epidemiology and pathophysiology of PD. .