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

项目摘要/摘要 帕金森氏病(PD)患者患癌症的风险通常较低，但有一个明显的例外- 黑色素瘤。帕金森病患者更容易患上黑色素瘤，而黑色素瘤患者在 发生帕金森病的风险较高。这种双向联系不仅在患者身上观察到，而且在 他们的亲属，表明这两个看似不同的过程具有共同的生物学成分。黑色素瘤是 与红发/白皙皮肤密切相关的黑素皮质素1受体功能丧失多态的表型 基因(MC1R)。我们之前曾报道过，红色头发的人和个人患帕金森病的风险更高 携带红发MC1R变种。携带MC1R失活突变的正常黑(C57BL/6)小鼠 (MC1Re/e小鼠)模仿红发人类，因为他们表现出红色/黄色的黑色素沉着和 依赖褐黑素的氧化性皮肤损伤和黑色素瘤易感性。这些红头发的老鼠也展示了 基础状态下氧化性脑损伤和多巴胺能缺乏症及加重的多巴胺能 包括α-突触核蛋白(α-SYN)在内的PD模型的毒性。MC1R在小鼠多巴胺能神经元中表达 黑质。MC1R的存在也被初步证实存在于大鼠的黑质。 人脑，散发性帕金森病患者信号减弱，与多巴胺能神经元丢失相关。 此外，红发人群中与帕金森病相关的较高死亡率已初步证实 人类群体。这个跨学科项目的总体目标是进一步阐明与黑色素瘤相关的 帕金森病患者的MC1R及靶向MC1R的神经保护作用 通过三个特定目标(SA)并行。SA1将确定红色色素沉着是否导致 黑质纹状体红发多巴胺能缺陷及儿茶酚胺能细胞是否需要MC1R 多巴胺能完整性。SA2将决定现有MC1R激动剂激活MC1R是否会保护 对抗α-SYN神经毒性以及这种保护是否是MC1R特异性的。SA3将分析红发和 黑色素瘤风险MC1R变异与健康人群中发展为帕金森病的风险增加相关 相同的变异是否与那些已经这样做的人的临床进展更快有关 被诊断为帕金森病。建立在流行病学和生物学证据的基础上，并以特殊的 跨学科的专业知识，这项拟议的研究有望建立因果关系的生物学似是而非 为MC1R(和褐黑素)和PD提供基础，从而为PD与黑色素瘤的关联提供洞察力。它的 这些发现将具有很高的翻译意义，可能会对帕金森病的治疗以及 关于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. .