The melanoma-linked "redhead" MC1R influences dopaminergic neuron survival.
The melanoma-linked "redhead" MC1R influences dopaminergic neuron survival.
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DOI：
10.1002/ana.24852
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发表时间：
2017-03
影响因子：
11.2
通讯作者：
Schwarzschild MA
中科院分区：
文献类型：
--
作者：
Chen X;Chen H;Cai W;Maguire M;Ya B;Zuo F;Logan R;Li H;Robinson K;Vanderburg CR;Yu Y;Wang Y;Fisher DE;Schwarzschild MA
患有帕金森病的人更有可能患上黑色素瘤，而黑色素瘤患者患帕金森病的风险也更高。黑色素瘤与红发/白皙皮肤密切相关，这是 MC1R（黑皮质素 1 受体）基因功能丧失多态性的一种表型。 MC1R 的功能丧失变异也与帕金森病风险增加有关。本研究旨在探讨 MC1R 在体内多巴胺能神经元中的作用。采用遗传和药理学方法来操纵 MC1R，并通过综合行为、神经化学和神经病理学测量来确定黑质纹状体多巴胺能完整性。 MC1Re/e 小鼠携带 MC1R 失活突变并模仿人类红发表型，其黑质纹状体多巴胺能神经元完整性受损，并且更容易受到多巴胺能神经元毒素 6-羟基多巴胺和 1-甲基-4-苯基-1,2,3,6-四氢吡啶的影响 （MPTP）。此外，选择性 MC1R 激动剂可防止 MPTP 诱导的多巴胺能神经毒性。我们的研究结果揭示了 MC1R 在黑质纹状体多巴胺能系统中的保护作用，并为 MC1R 作为帕金森病的潜在治疗靶点提供了理论基础。连同其在黑色素瘤中的既定作用，MC1R 可能代表黑色素瘤和帕金森病的常见致病途径。
Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo. Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures. MC1Re/e mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP-induced dopaminergic neurotoxicity. Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease.
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影响因子：
14.8
作者：
Jackson-Lewis, Vernice;Przedborski, Serge
通讯作者：
Przedborski, Serge
影响因子：
3.7
作者：
Matsuo Y;Kamitani T
通讯作者：
Kamitani T
影响因子：
4.2
作者：
Gan-Or Z;Mohsin N;Girard SL;Montplaisir JY;Ambalavanan A;Strong S;Mallett V;Laurent SB;Bourassa CV;Boivin M;Langlois M;Arnulf I;Högl B;Frauscher B;Monaca C;Desautels A;Gagnon JF;Postuma RB;Dion PA;Dauvilliers Y;Dupre N;Alcalay RN;Rouleau GA
通讯作者：
Rouleau GA
DOI：
10.1016/s1474-4422(15)00006-x
发表时间：
2015-08
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Dehay B;Bourdenx M;Gorry P;Przedborski S;Vila M;Hunot S;Singleton A;Olanow CW;Merchant KM;Bezard E;Petsko GA;Meissner WG
通讯作者：
Meissner WG
影响因子：
7.4
作者：
Hazell GG;Hindmarch CC;Pope GR;Roper JA;Lightman SL;Murphy D;O'Carroll AM;Lolait SJ
通讯作者：
Lolait SJ