色素基因MC1R对多巴胺能神经元的生存调控及其在帕金森病中的神经保护作用

Melanocortin 1 receptor (MC1R) is a key pigmentation gene，andits loss-of-function mutations are associated with red hair／fair skin, compromised UV protection, and increased melanoma risk. Loss-of-function red hair/fair skin variants of MC1R have also been found to be associated with increased risk for Parkinson's disease (PD). Moreover, there is a bidirectional, positive link between PD and melanoma, not only in the patients themselves but also in their relatives, strongly suggesting a genetic basis for the link between these two seemingly distinct conditions. Despite the relatively low morbidity of melanoma, loss-of-function MC1R variants have been reported in East Asians. In C57 black mice, an inactivating mutation of MC1R (MC1Re/e mice) results in a phenotype analogous to red hair in humans. These mice also display oxidative stress damage in skin and a tendency to develop melanoma. Conversely transgenic human MC1R expression (MC1RTg mice) rescues the skin phenotype. Our preliminary data indicate expression of MC1R in dopaminergic neurons of the substantianigra, and reduced striatal dopamine under basal conditions in MC1Re/e mice. Furthermore, MC1Re/e mice demonstrate exacerbated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and 6-hydroxydopamine (6-OHDA)-induced rotational behavior. In collaboration with leading researchers who reported MC1R mediated pigmentation and melanoma carcinogenesis, we propose to investigate the role of MC1R in dopaminergic neuron survival and pathophysiology of PD, and of particular translational relevance, the neuroprotective potential of human MC1R. Complementary MC1Re/e mice and MC1RTg mice will be used to systematically assess whether MC1Re/e mice display dopaminergic neuronal deficits under basal conditions and exacerbated dopaminergic phenotypesin a transgenic mouse model of PD overexpressing α-synuclein，and conversely whetherMC1RTg mice have preserved dopaminergic neuronal integrity and attenuated neurotoxicity.Possible involvement of oxidative stress will also be explored. Based on compelling epidemiological and laboratory evidence, the proposed study strikes a balance between reasonable risk and high return. Results of the study may provide conceptually novel and clinically relevant insights into pathophysiology,epidemiology, and therapeutics of PD.They may also facilitate further collaborative investigations on a dual role of MC1R in melanocytes and dopaminergic neurons and potential of exploring skin pigmentation as a biomarker and MC1R targeting as a novel therapeutic strategy for PD.

黑素皮质素受体1(MC1R)调控皮肤色素生成，该基因失活突变导致红头发、浅肤色和高黑色素瘤风险，而这组人群也正是帕金森病发病的高风险人群。此外，帕金森病与黑色素瘤病人尤其是亲属的交互易感更提示这两种疾病或存共同遗传机制。东亚人群虽然黑色素瘤发病率低但同样存在MC1R失活突变。MC1R失活突变（MC1Re/e）致黑小鼠变为黄红色并具自发黑色素瘤倾向，而MC1R转基因（Tg)则使毛色再逆转为黑色。本课题前期结果证明MC1R在黑质多巴胺能神经元表达，而且MC1Re/e小鼠纹状体多巴胺含量下降，这类小鼠还表现对多巴胺能神经毒素的较高敏感性。本研究在此基础上与国际色素调控及皮肤临床知名学者合作，利用MC1Re/e和MC1R Tg小鼠模型探索MC1R在基础状态和在α-synuclein转基因帕金森病模型中对多巴胺能神经元的支持保护作用及其可能机制。研究结果将为帕金森病提供崭新理论视角和全新治疗靶点。

黑素皮质素受体1(MC1R)调控皮肤色素生成,该基因失活突变导致红头发、浅肤色和高黑 色素瘤风险,而这组人群也正是帕金森病发病的高风险人群。此外,帕金森病与黑色素瘤 病人尤其是亲属的交互易感更提示这两种疾病或存共同遗传机制。东亚人群虽然黑色素瘤 发病率低但同样存在MC1R失活突变。MC1R失活突变(MC1Re/e)致黑小鼠变为黄红色并具 自发黑色素瘤倾向,而MC1R转基因(Tg)则使毛色再逆转为黑色。本项目旨在探索：1）MC1R 在脑内尤其是黑质纹状体多巴胺能神经元中的表达； 2）MC1R 基因失活突变与转基因表达在基础状态对黑质纹状体多巴胺能神经系统形态和功能的影响；3） MC1Re/e 和MC1RTg 小鼠对帕金森病相关基因 α-synuclein 过度表达的易感性变化；4）MC1R 基因失活突变与转基因表达在基础状态下以及在α-synuclein 模型中对黑质纹状体氧化应激状态的影响。项目在研四年间进展顺利，结果发现 MC1Re/e 小鼠在基础状态下即显示黑质纹状体多巴胺系统的高氧化应激状态与功能形态异常，在α-Synuclien 模型中则表现出较高易感性；而与此相反，MC1R Tg 小鼠黑质纹状体多巴胺系统具有正常氧化应激状态和正常形态功能，同时对α-Synuclien 的致病作用具有较高防御保护能力。项目部分结果发表后被国际主流媒体广泛报道。这些发现加深了帕金森病病理生理和发病机制的理解、为多巴胺与皮肤色素调控的共同生物遗传学基础提供了全新认识，同时为以MC1R 为靶向的神经保护治疗提供了理论依据。