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

黑色素瘤-帕金森病联系的 MC1R 基础和 MC1R 的神经保护潜力

• 批准号: 10373117
• 负责人: Xiqun Chen
• 金额: $ 35.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373117
• 关键词: Agonist; Alleles; Animal Model; Back; Biological; Brain; Brain Injuries; C57BL/6 Mouse; Cells; Clinical; Cytoprotection; Diagnosis; Discipline; Disease; Dopamine; Enzymes; Epidemiology; Event; Exhibits; Functional disorder; Future; Gene Activation; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Polymorphism; Goals; Hair; Hair Color; Human; Individual; Investigation; Knockout Mice; Laboratories; Link; MPTP Poisoning; Malignant Neoplasms; Melanins; Melanocortin 1 Receptor; Modeling; Monophenol Monooxygenase; Mus; Mutant Strains Mice; Mutation; Outcome; Oxidative Stress; Parkinson Disease; Pathologic; Pathway interactions; Patients; Pharmacology; Phenotype; Pigmentation physiologic function; Pigments; Population; Predisposition; Process; Receptor Gene; Reporting; Resources; Risk; Role; Signal Transduction; Signaling Protein; Skin; Substantia nigra structure; System; Therapeutic; Toxic effect; Tyrosine 3-Monooxygenase; Variant; Wild Type Mouse; afamelanotide; alpha synuclein; clinical investigation; cohort; disorder risk; dopaminergic neuron; epidemiology study; genetic variant; high risk; insight; loss of function; melanoma; mortality; mutant; neuroprotection; neurotoxicity; new therapeutic target; nigrostriatal system; novel; oxidative damage; pheomelanin; skin damage; translational potential

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. .

项目总结/文摘

项目成果

Probable Parasomnias and Mortality: A Prospective Study in US Men.

可能的异态睡眠和死亡率：对美国男性的前瞻性研究。

• DOI: 10.1016/j.mayocp.2023.06.018
• 发表时间: 2023
• 期刊: Mayo Clinic proceedings
• 影响因子: 8.9
• 作者: Zhang,Xinyuan;Molsberry,SamanthaA;Pavlova,Milena;Schwarzschild,MichaelA;Ascherio,Alberto;Gao,Xiang
• 通讯作者: Gao,Xiang

Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease.

• DOI: 10.1016/j.ebiom.2018.10.039
• 发表时间: 2018-11
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Chen X;Umeh CC;Tainsh RE;Feng DD;Maguire M;Zuo F;Rahimian M;Logan R;Wang X;Ascherio A;Macklin EA;Buys ES;Schwarzschild MA;Parkinson Study Group (PSG) The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) investigators
• 通讯作者: Parkinson Study Group (PSG) The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) investigators

Parkinson's disease and cancer: a systematic review and meta-analysis of over 17 million participants.

• DOI: 10.1136/bmjopen-2020-046329
• 发表时间: 2021-07-02
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Zhang X;Guarin D;Mohammadzadehhonarvar N;Chen X;Gao X
• 通讯作者: Gao X

Association of caffeine and related analytes with resistance to Parkinson disease among LRRK2 mutation carriers: A metabolomic study.

• DOI: 10.1212/wnl.0000000000010863
• 发表时间: 2020-12-15
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Crotty GF;Maciuca R;Macklin EA;Wang J;Montalban M;Davis SS;Alkabsh JI;Bakshi R;Chen X;Ascherio A;Astarita G;Huntwork-Rodriguez S;Schwarzschild MA
• 通讯作者: Schwarzschild MA

Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson's disease.

• DOI: 10.1186/s13024-022-00520-4
• 发表时间: 2022-02-23
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Cai W;Srivastava P;Feng D;Lin Y;Vanderburg CR;Xu Y;Mclean P;Frosch MP;Fisher DE;Schwarzschild MA;Chen X
• 通讯作者: Chen X