title: The melanoma-linked "redhead" MC1R influences dopaminergic neuron survival.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures.
  
  
  RESULTS
  MC1Re/emice, 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.
  
  
  CONCLUSIONS
  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. Ann Neurol 2017;81:395-406.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.|Shanghai 10th Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xiqun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Boston, MA.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Chen
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Waijiao
authors.initials: W
authors.lastname: Cai
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Michael
authors.initials: M
authors.lastname: Maguire
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Bailiu
authors.initials: B
authors.lastname: Ya
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Fuxing
authors.initials: F
authors.lastname: Zuo
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Robert
authors.initials: R
authors.lastname: Logan
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Boston, MA.
authors.forename: Katey
authors.initials: K
authors.lastname: Robinson
authors.affiliation: Harvard Neurodiscovery Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Vanderburg
authors.affiliation: Department of Chemistry, University of California, Riverside, CA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Chemistry, University of California, Riverside, CA.
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Boston, MA.
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics; D010858:Pigmentation / Q000235:genetics*; D044102:Receptor, Melanocortin, Type 1 / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
chemical_list: D009498:Neurotoxins; D044102:Receptor, Melanocortin, Type 1; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine